Background: Hypertriglyceridaemia is common in patients with HIV, especially those taking protease inhibitors or with lipodystrophy, frequently observed at levels associated with accelerated cardiac disease. This study aimed to explore the efficacy and safety of gemfibrozil for hypertriglyceridemia in patients with HIV infection. Methods: A 16-week, randomized, double-blind, comparative study of low saturated fat diet versus low saturated fat diet with gemfibrozil 600 mg twice daily in patients with triglycerides ≥ 3mmol/l receiving protease inhibitor therapy. Following a 4-week period of dietary intervention alone, patients were randomized to gemfibrozil or matching placebo. The primary outcome was the difference in mean change in fasting triglycerides at week 16 between the two groups. Results: 37 men were randomized (17 gemfibrozil, 20 placebo) with median fasting triglycerides 5.6 mmol/l. Mean changes in triglycerides from week 4 to week 16 were -1.22 mmol/l and +0.35 mmol/l for the gemfibrozil and placebo groups respectively (between-group mean difference of 1.57 retool/l; 95% confidence interval, -6.7 to 3.5; P = 0.08). Only one patient treated had triglycerides return to a desirable range (≤ 2.00 mmol/l). No significant changes in the other metabolic parameters were observed. Gemfibrozil was well tolerated, did not appear to induce additional protease inhibitor toxicity, and did not induce changes in CD4 lymphocyte counts or HIV RNA load. Conclusions: Gemfibrozil is safe and demonstrated at most, modest efficacy for hypertriglyceridemia in HIV-infected patients receiving protease inhibitors. Given the level of response, however, it is unclear whether these reductions will confer clinical benefit, at least in the presence of continued protease inhibitor use.