Background: Antiretroviral drugs have been associated with changes in fat metabolism including lipids, fat mass and fat distribution. In HIV treatment, tenofovir disoproxil fumarate (TDF) has been shown to have a more favorable metabolic profile than other drugs in its class. However, the metabolic effects of TDF used as PrEP have not been reported. Methods: We evaluated the effects of TDF/FTC on lipids and body composition in participants in a blinded placebo controlled PrEP trial. Participants enrolled in a metabolic subcohort (N=251, TDF/FTC; N=247, placebo) consented to fasting lipid panels, dual-energy X-ray absorptiometry (DXA) scans for body composition and pharmacologic testing of plasma and intracellular tenofovir diphosphate levels at baseline and every 24 weeks thereafter. Results: Lean body mass was stable and unaffected by TDF/FTC. Body weight increased in both groups but was lower on TDF/FTC through week 72. This difference was explained by lower fat accumulation on TDF/FTC. The net median percent difference (SE, p-value) for TDF/FTC v. placebo at week 24 was -0.8% (0.4%, p=0.02), +0.3% (0.4%, p=0.46), -3.8% (1.4%, p=0.009) for total, lean and fat mass, respectively. There was no apparent differential regional fat accumulation on TDF/FTC. Decreases in cholesterol, but not triglycerides, were seen in TDF/FTC participants with detectable drug levels compared with placebo. Conclusions: TDF/FTC for PrEP showed cholesterol reductions and appeared to transiently suppress the accumulation of weight and body fat, compared to placebo. There was no evidence of altered fat distribution or lipodystrophy during daily oral TDF/FTC PrEP.