Introduction: Previous studies have described improvements on lipid parameters when switching from other antiretroviral drugs to tenofovir (TDF) and impairments in lipid profile when discontinuing TDF. [13] It is unknown, however, if TDF has an intrinsic lipid-lowering effect or such findings are due to the addition or removal of other offending agents or other reasons. Materials and Methods: This was a randomized, crossover, double-blind, placebo-controlled clinical trial (NCT 01458977). Subjects with HIV-1 RNA B50 copies/mL during at least 6 months on stable DRV/r (800/100 mg QD) or LPV/r (400/100 mg BID) monotherapy, with confirmed fasting total cholesterol ]200 or LDL-cholesterol ]130 mg/dL and not taking lipid-lowering drugs were randomized to (A) adding TDF/FTCduring 12 weeks followed by 24 weeks without TDF/FTC, or (B) continuing without TDF/FTC for 12 weeks, adding TDF/FTC for 12 weeks and then withdrawing TDF/FTC for 12 additional weeks. Randomization was stratified by DRV/r or LPV/r use at study entry. All subjects received a specific dietary counselling. Primary endpoints were changes in median fasting total, LDL and HDL-cholesterol 12 weeks after TDF/FTC addition. Analyses were performed by ITT. Results: 46 subjects with a median age of 43 (4048) years were enrolled in the study: 70% were male, 56% received DRV/r and 44% LPV/r. One subject withdrew the study voluntarily at week 4 and another one interrupted due to diarrhoea at week 24. Treatment with TDF/FTC decreased total, LDL and HDL-cholesterol from 235.9 to 204.9 (pB0.001), 154.7 to 127.6 (pB0.001) and 50.3 to 44.5 mg/dL (pB0.001), respectively. In comparison, total, LDL and HDL-cholesterol levels remained stable during placebo exposure. Week 12 total cholesterol (pB0.001), LDL-cholesterol (pB0.001) and HDL-cholesterol (p0.011) levels were significantly lower in TDF/FTC versus placebo. Treatment with TDF/FTC reduced the fraction of subjects with abnormal fasting total-cholesterol (]200 mg/dL) from 86.7% to 56.8% (p0.001) and LDL-cholesterol (]130 mg/dL) from 87.8% to 43.9% (pB0.001), which was not observed with placebo. There were no virological failures, and CD4 and triglyceride levels remained stable regardless of exposure. Conclusion: Coformulated TDF/FTC has an intrinsic lipid-lowering effect, likely attributable to TDF