Simplified drug regimens may improve retention in care for chronic diseases. In April 2013, South Africa adopted a once-daily single-pill HIV treatment regimen as standard-of-care, replacing a multiple-pill regimen. Because the regimens had similar biological efficacy, the shift to single-pill therapy offers a real-world test of the impact of simplified drug delivery mechanisms on patient behavior. Using a quasi-experimental regression discontinuity design, we assessed retention in care among patients starting HIV treatment just before and just after the guideline change. The study included 4484 patients starting treatment at a large public sector clinic in Johannesburg, South Africa. The share of patients prescribed a single-pill regimen increased by over 40 percentage points between March and April 2013. Initiating after the policy change was associated with 11.7 percentage points higher retention at 12 months (95% CI: -2.2, 29.4). Findings were robust to different measures of retention, different bandwidths, and different statistical models. Patients starting treatment early in HIV infection - a key population in the test-and-treat era - experienced the greatest improvements in retention from single-pill regimens.