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Background:. The optimal approach for total hip arthroplasty (THA) remains hotly debated. While wound complications following the direct anterior approach are higher than with other approaches, the organism profile of periprosthetic joint infections (PJIs) by approach remains unknown. Our goal was to compare the organism profiles of PJIs following direct anterior and non-anterior THA. Methods:. We retrospectively reviewed 12,549 primary THAs (4,515 direct anterior and 8,034 non-anterior) that had been performed between January 2012 and September 2019 at a university-affiliated single-specialty orthopaedic hospital to identify patients with an early postoperative PJI. Criteria used for the diagnosis of a PJI were the National Healthcare Safety Network, which screens for PJI that occurs within 90 days of index arthroplasty, and the Musculoskeletal Infection Society guidelines. Patient demographic information and organism characteristics were recorded for analysis. Results:. We identified 84 patients (38 who underwent the direct anterior approach and 46 who underwent the non-anterior approach) with an early postoperative PJI following primary THA (0.67% total THA PJI rate, 0.84% direct anterior THA PJI rate, and 0.57% non-anterior THA PJI rate). The direct anterior THA cohort had a significantly lower body mass index and American Society of Anesthesiologists score than the non-anterior THA cohort (29.5 versus 35.2 kg/m2, p < 0.0001; 2.29 versus 2.63, p = 0.016, respectively). Regarding organism profile, patients in the direct anterior THA cohort had significantly more monomicrobial gram-negative infections than the non-anterior THA cohort (4 versus 0, p = 0.038). We did not identify any demographic risk factors other than approach for gram-negative PJI. There were no significant differences in methicillin-resistant Staphylococcus aureus, methicillin-sensitive Staphylococcus aureus, coagulase-negative Staphylococcus, obligate anaerobes, polymicrobial, or PJIs due to other organisms by approach. Conclusions:. Direct anterior THA approaches have a greater risk of monomicrobial gram-negative PJI, likely due to the unique microbiome of the inguinal region. While targeted infection prophylaxis may reduce these infections, it is not entirely effective on its own. Future studies with larger sample sizes are required to help us develop more targeted perioperative infection prophylaxis. Level of Evidence:. Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.