Patients on antiretroviral therapy are reported to have an increased risk of cardiovascular disease. We aimed to investigate the effect of n-3 polyunsaturated fatty acids (n-3 PUFAs) on plasma lipids, lipoproteins and inflammatory markers in HIV-infected patients treated with antiretroviral therapy. We randomized 51 patients in a placebo-controlled, double-blind trial to receive either 2 capsules of Omacor twice daily or 2 capsules of placebo. Compliance was measured by determining levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in neutrophils. Plasma triglycerides were reduced in the n-3 PUFA group by 0.14 mmol/l after 12 weeks of treatment (n=26), while plasma triglycerides increased by 0.36 mmol/l in the control group (n=25). The difference between groups was significant, p=0.03. No significant effect of treatment was found for total cholesterol, high-density lipoprotein (HDL) or low-density lipoprotein (LDL) cholesterol or apolipoproteins. There was a significant increase in leukotriene B5 (LTB5) and LTB5/LTB4 ratio in the n-3 PUFA group compared to the control group. Baseline values for intercellular adhesion molecule-1 (ICAM), vascular cell adhesion molecule-1 (VCAM) and highly sensitive C-reactive protein (hsCRP) were comparable at baseline, and the intervention did not change these parameters significantly. The present study showed that treatment with n-3 PUFA slightly decreased plasma triglycerides and induced anti-inflammatory effects by increasing formation of anti-inflammatory LTB5.