BACKGROUND: This study was designed to evaluate the effects of omega-3 fatty acids supplements and simvastatin on lipoproteins and heart rate variability (HRV), a surrogate parameter of cardiac autonomic function, in patients with mixed dyslipidemia. METHODS: This study was a prospective, randomized, open-label study. Among the 171 patients screened, 62 who met the inclusion criteria after 6 weeks on a strict diet therapy were randomized into two treatment groups. The inclusion criteria were mixed dyslipidemia with a high triglyceride level (200-499 mg per 100 ml) and a total cholesterol level >200 mg per 100 ml. After a run-in period of 6 weeks, the patients were randomized into two groups and given a combination treatment with 4 g of omega-3 fatty acids (four 1 g Omacor (eicosapentaenoic acid, 465 mg; docosahexaenoic acid, 375 mg; other omega-3 fatty acids, 60 mg; others 100 mg, Gun-il Pharmacy, Seoul, Korea)) and 20 mg of simvastatin daily or a monotherapy of 20 mg simvastatin for 6 weeks. In the combination therapy group, seven patients dropped out, and in the simvastatin alone therapy group, five patients dropped out during the study period. RESULTS: After 6 weeks of drug treatment, triglyceride levels decreased by 41.0% in the combination treatment group and 13.9% in the simvastatin monotherapy group (from 309.2 +/- 95 mg per 100 ml to 177.7 +/- 66 versus 294.6 +/- 78 mg per 100 ml to 238.3 +/- 84 mg per 100 ml, respectively, P = 0.0007). No significant changes in the HRV parameters were observed in either group. CONCLUSION: The combination of omega-3 fatty acids plus simvastatin, which achieved a significantly greater reduction of triglycerides without adverse reactions, should be considered as an optimal treatment option for patients with mixed dyslipidemia.