Background: Metabolic syndrome (MS) is characterized with insulin resistance and systemic inflammation.We investigated the effects the systemic inflammation and insulin resistance after supplement with N-3 polyunsaturated fatty acid (N-3 PUFA) in patients with MS. We also evaluated the dose dependent effects of N-3 PUFA on improving systemic inflammation and insulin resistance by comparing 2 g/day (conventional dose) with 4 g/day (high dose) of N-3 PUFA. Methods: Subjects with MS defined by ATP-III criteria were randomly enrolled in placebo and N-3 PUFA groups. The N-3 PUFA group received 2 g of N-3 PUFA from baseline to 6 weeks, and 4 g of N-3 PUFA from 6 to 12 weeks. We measured fasting serum lipid profiles, high sensitivity C-reactive protein (hs-CRP), interleukin-6, tumor necrosis factor-慣, fasting insulin and glucose at baseline, and 6 and 12 weeks. Insulin resistance was calculated using the homeostasis model assessment of insulin resistance (HOMA-IR) equation. A repeated measures analysis of variance (ANOVA) was used to analyze inter- and intra-group differences between N-3 PUFA and placebo group and dose-dependent effects of N-3 PUFA. Results: 53 (N-3 PUFA, N=26 and placebo, N=27) out of 60 subjects completed this study. Baseline clinical and laboratory characteristics were similar in both groups. N-3 PUFA administration significantly lowered mean hs-CRP compared with placebo group (p = 0.01, Fig.). There was no significant dose-dependent effect of N-3 PUFA on mean hs-CRP reduction. Improvements of mean HOMA-IR after N-3 PUFA administration were significant compared with placebo group (p = 0.03, Fig.). Also there was significant dose-dependent effect of N-3 PUFA on mean HOMA-IR in N-3 PUFA group (p = 0.000, Fig.). Conclusions: N-3 PUFA administration in patients with the MS showed significant reduction in serum hs-CRP and insulin resistance compared with placebo. In addition, the improvement of insulin resistance was significantly related to dose-dependent effect of N-3 PUFA.