Background High rates of patient attrition from care between HIV testing and antiretroviral therapy (ART) initiation have been documented in sub-Saharan Africa, contributing to persistently low CD4 cell counts at treatment initiation. One reason for this is that starting ART in many countries is a lengthy and burdensome process, imposing long waits and multiple clinic visits on patients. We estimated the effect on uptake of ART and viral suppression of an accelerated initiation algorithm that allowed treatment-eligible patients to be dispensed their first supply of antiretroviral medications on the day of their first HIV-related clinic visit. Methods and Findings RapIT (Rapid Initiation of Treatment) was an unblinded randomized controlled trial of single-visit ART initiation in two public sector clinics in South Africa, a primary health clinic (PHC) and a hospital-based HIV clinic. Adult (≥18 y old), non-pregnant patients receiving a positive HIV test or first treatment-eligible CD4 count were randomized to standard or rapid initiation. Patients in the rapid-initiation arm of the study (“rapid arm”) received a point-of-care (POC) CD4 count if needed; those who were ART-eligible received a POC tuberculosis (TB) test if symptomatic, POC blood tests, physical exam, education, counseling, and antiretroviral (ARV) dispensing. Patients in the standard-initiation arm of the study (“standard arm”) followed standard clinic procedures (three to five additional clinic visits over 2–4 wk prior to ARV dispensing). Follow up was by record review only. The primary outcome was viral suppression, defined as initiated, retained in care, and suppressed (≤400 copies/ml) within 10 mo of study enrollment. Secondary outcomes included initiation of ART ≤90 d of study enrollment, retention in care, time to ART initiation, patient-level predictors of primary outcomes, prevalence of TB symptoms, and the feasibility and acceptability of the intervention. A survival analysis was conducted comparing attrition from care after ART initiation between the groups among those who initiated within 90 d. Three hundred and seventy-seven patients were enrolled in the study between May 8, 2013 and August 29, 2014 (median CD4 count 210 cells/mm3). In the rapid arm, 119/187 patients (64%) initiated treatment and were virally suppressed at 10 mo, compared to 96/190 (51%) in the standard arm (relative risk [RR] 1.26 [1.05–1.50]). In the rapid arm 182/187 (97%) initiated ART ≤90 d, compared to 136/190 (72%) in the standard arm (RR 1.36, 95% confidence interval [CI], 1.24–1.49). Among 318 patients who did initiate ART within 90 d, the hazard of attrition within the first 10 mo did not differ between the treatment arms (hazard ratio [HR] 1.06; 95% CI 0.61–1.84). The study was limited by the small number of sites and small sample size, and the generalizability of the results to other settings and to non-research conditions is uncertain. Conclusions Offering single-visit ART initiation to adult patients in South Africa increased uptake of ART by 36% and viral suppression by 26%. This intervention should be considered for adoption in the public sector in Africa. Trial Registration ClinicalTrials.gov NCT01710397, and South African National Clinical Trials Register DOH-27-0213-4177., In the RapIT randomized controlled trial, Sydney Rosen and colleagues investigate whether accelerated initiation of antiretroviral therapy can improve viral suppression for HIV patients in South Africa., Author Summary Why Was This Study Done? One of the most persistent operational challenges facing antiretroviral therapy (ART) programs for HIV/AIDS in sub-Saharan Africa is late presentation of patients for care and high rates of attrition from care between HIV testing and ART initiation. One reason for this is that starting ART in many countries is a lengthy and burdensome process, imposing long waits and multiple clinic visits on patients; in South Africa, the country with the world’s largest HIV treatment program, patients must typically make five or six clinic visits, starting with an HIV test, before they receive medications. There have not yet been any controlled evaluations of an integrated, rapid HIV treatment initiation algorithm that allows patients to initiate ART in a single clinic visit, so the RapIT trial was done to find out if “same-day initiation” of ART would increase the number of patients starting treatment and improve overall health outcomes, compared to current practices. What Did the Researchers Do and Find? We randomly assigned 377 adult patients at two public clinics in Johannesburg, South Africa, who had provided consent to participate in the study to one of two groups. Patients in the group assigned to receive rapid treatment initiation were offered the chance to start treatment on the same day as their first clinic visit, using rapid, point-of-care laboratory tests and an accelerated sequence of other steps, including a physical exam, education, and counseling. Patients in the group assigned to receive standard treatment initiation followed the standard schedule for treatment initiation used by the clinics, which usually required three to five additional clinic visits over a 2–4 wk period. After the study enrollment visit, patients were followed up by reviewing their regular clinic medical records, to determine how many did start treatment and how many were still in care and had good outcomes, as indicated by a suppressed viral load, 10 mo later. We found that 97% of patients in the rapid initiation group had started ART by 90 d after study enrollment—three-quarters of them on the same day—compared to 72% of patients in the standard initiation group. By 10 mo after study enrollment, 64% of patients in the rapid group had good outcomes compared to 51% in the standard group. Rapid initiation group patients spent roughly two and a half hours in the clinic to complete all the steps required before they got their medications. What Do These Findings Mean? The RapIT (Rapid Initiation of Treatment) trial showed that it is possible to initiate nearly all eligible patients on HIV therapy, and to do so in a much shorter time interval than previously required. By showing that offering the opportunity to start treatment on the spot, without delay, overcomes many barriers patients would otherwise face, this study demonstrates that same-day ART initiation is an effective strategy for improving health outcomes. More patients in the rapid initiation group dropped out of care after starting treatment than in the standard initiation group; although the rapid initiation group still had better health outcomes overall, adherence support after starting treatment remains essential. The findings of this study are limited because the study took place in only two clinics in one part of South Africa and was carried out by study staff, not by regular clinic staff. Based on this study’s results, consideration could be given to accelerating the process of ART initiation in many different settings and for different types of patients.