BACKGROUND: Antiretroviral agents, particularly protease inhibitors (PIs), may adversely affect lipid levels in patients with HIV infection. However, it is not known whether HIV-associated dyslipidemia is more difficult to treat. OBJECTIVE: To compare the effectiveness and safety of lipid-lowering therapy in patients with and without HIV infection. DESIGN: Retrospective cohort study. SETTING: Integrated health care delivery system from 1996 to 2005. PATIENTS: 829 patients with HIV infection and 6941 patients without HIV infection beginning lipid-lowering therapy for elevated low-density lipoprotein cholesterol or triglyceride levels. MEASUREMENTS: Percentage change in lipids within 12 months and adverse liver- and muscle-related clinical and laboratory events. RESULTS: Compared with patients without HIV infection, patients with HIV infection beginning statin therapy had smaller reductions in low-density lipoprotein cholesterol levels (25.6% vs. 28.3%; P = 0.001), which did not vary by antiretroviral therapy class. Patients with HIV infection beginning gemfibrozil therapy had substantially smaller reductions in triglyceride levels than patients without HIV infection (44.2% vs. 59.3%; P < 0.001), and reductions with gemfibrozil varied by antiretroviral therapy class (44.0% [P = 0.001] in patients receiving PIs only, 26.4% [P < 0.001] in patients receiving PIs and nonnucleoside reverse transcriptase inhibitors [NNRTIs], and 60.3% [P = 0.94] in patients receiving NNRTIs only). Rhabdomyolysis was diagnosed in 3 patients with HIV infection and 1 patient without HIV infection. No clinically recognized cases of myositis or myopathy were observed. The risk for laboratory adverse events was low (<5%), although it was increased in patients with HIV infection. Limitations: Laboratory measurements were not uniformly performed according to HIV status, and adequate fasting before lipoprotein testing could not be verified. Results may not be completely generalizable to uninsured persons, women, or certain racial or ethnic minorities. CONCLUSION: Dyslipidemia, particularly hypertriglyceridemia, is more difficult to treat in patients with HIV infection than in the general population. However, patients with HIV infection receiving NNRTI-based antiretroviral therapy and gemfibrozil had triglyceride responses similar to those in patients without HIV infection. Funding: GlaxoSmithKline.