Background A major barrier to achieving ambitious targets for global control of HIV and hepatitis C virus (HCV) is low levels of awareness of infection among key populations such as men who have sex with men (MSM) and people who inject drugs (PWID). We explored the potential of a strategy routinely used for surveillance in these groups, respondent-driven sampling (RDS), to be used as an intervention to identify HIV- and HCV-infected PWID and MSM who are unaware of their status and those who are viremic across 26 Indian cities at various epidemic stages. Methods and findings Data were collected as part of the baseline assessment of an ongoing cluster-randomized trial. RDS was used to accrue participants at 27 sites (15 PWID sites and 12 MSM sites) selected to reflect varying stages of the HIV epidemic among MSM and PWID in India. A total of 56 seeds recruited a sample of 26,447 persons (approximately 1,000 participants per site) between October 1, 2012, and December 19, 2013. Across MSM sites (n = 11,997), the median age was 25 years and the median number of lifetime male partners was 8. Across PWID sites (n = 14,450), 92.4% were male, the median age was 30 years, and 87.5% reported injection in the prior 6 months. RDS identified 4,051 HIV-infected persons, of whom 2,325 (57.4%) were unaware of their HIV infection and 2,816 (69.5%) were HIV viremic. It also identified 5,777 HCV-infected persons, of whom 5,337 (92.4%) were unaware that they were infected with HCV and 4,728 (81.8%) were viremic. In the overall sample (both MSM and PWID), the prevalence of HIV-infected persons who were unaware of their status increased with sampling depth, from 7.9% in participants recruited in waves 1 through 5 to 12.8% among those recruited in waves 26 and above (p-value for trend < 0.001). The overall detection rate of people unaware of their HIV infection was 0.5 persons per day, and the detection rate of HIV-infected persons with viremia (regardless of their awareness status) was 0.7 per day. The detection rate of HIV viremic individuals was positively associated with underlying HIV prevalence and the prevalence of HIV viremia (linear regression coefficient per 1-percentage-point increase in prevalence: 0.05 and 0.07, respectively). The median detection rate of PWID who were unaware of their HCV infection was 2.5 per day. The cost of identifying 1 unaware HIV-infected individual ranged from US$51 to US$2,072 across PWID sites and from US$189 to US$5,367 across MSM sites. The mean additional cost of identifying 1 unaware HCV-infected PWID was US$13 (site range: US$7–US$140). Limitations of the study include the exclusivity of study sites to India, lack of prior HIV/HCV diagnosis confirmation with clinic records, and lack of cost data from other case-finding approaches commonly used in India. Conclusions In this study, RDS was able to rapidly identify at nominal cost a substantial number of unaware and viremic HIV-infected and HCV-infected individuals who were currently not being reached by existing programs and who were at high risk for transmission. Combining RDS (or other network-driven recruitment approaches) with strategies focused on linkage to care, particularly in high-burden settings, may be a viable option for achieving the 90-90-90 targets in key populations in resource-limited settings., In a large cross-sectional study done in India, Sunil Solomon and colleagues report on respondent-driven sampling for identification of HIV and HCV infections., Author summary Why was this study done? Men who have sex with men (MSM) and people who inject drugs (PWID) bear a high burden of HIV and HCV, and fall behind other at-risk groups in achieving Joint United Nations Programme on HIV/AIDS (UNAIDS) 90-90-90 targets. The behaviors of PWID and MSM (injection drug use and engagement in same-sex relationships) are highly stigmatized in many low- and middle-income countries, resulting in large segments of these populations being hidden. Finding PWID and MSM who are HIV-infected but unaware of their status and not in treatment is critical to curbing the HIV epidemic. What did the researchers do and find? We used data collected as part of an ongoing cluster-randomized trial to explore the potential of respondent-driven sampling (RDS), a chain-referral recruitment strategy, to be used as an intervention to identify unaware and viremic HIV-infected MSM and PWID across 26 Indian cities. We further evaluated the potential of incorporating hepatitis C virus (HCV) testing for PWID. RDS was effective in identifying unaware and viremic HIV-infected MSM and PWID, as well as unaware and viremic HCV-infected PWID. The longer RDS ran (more waves), the more likely it was to identify unaware and viremic HIV-infected MSM and PWID. RDS was most effective in settings with high HIV and HCV burden and low service availability. Incorporating HCV testing into HIV programs for PWID is a cost-effective way of identifying PWID unaware of their HCV infection. What do these findings mean? As the HIV community embraces the UNAIDS 90-90-90 targets, respondent-driven recruitment could be a critical tool in achieving the first 90 target among MSM and PWID in low-and-middle-income countries. Programs targeting drug-using populations should consider combining HIV and HCV screening for maximal benefit to the population.