BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a major risk factor for type 2 diabetes, cardiovascular disease, and liver failure. Treatment with n-3 long-chain polyunsaturated fatty acids (n-3 LCPUFAs) produced variable success in improving NAFLD. The purpose of this review is to determine if n-3 LCPUFA will decrease markers of NAFLD, compare the efficacies of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and identify factors that contribute to discrepancies in results. METHODS: This study reviewed published clinical studies with n-3 LCPUFA and NAFLD/nonalcoholic steatohepatitis (NASH) by using PubMed and Web of Science. RESULTS: Seventeen human studies ranging in DHA 250 mg/day to a mixture of EPA+DHA 50 mL/day for 8 weeks to 2 years were identified. Results obtained varied because of different dosages of n-3 LCPUFA, EPA and DHA ratios, duration, subject characteristics, diet, exercise, compliance, methods, and other factors. Despite inconsistencies in the results reported, 13 of 17 published studies reported that n-3 LCPUFA supplementation decreased liver fat, liver enzymes, or markers of inflammation; four reported decrease in ballooning and two in fibrosis. Results also indicated that DHA was more effective than EPA in the treatment of NAFLD. Caloric restriction and supplementation with n-3 LCPUFA were additive in decreasing hepatic steatosis. CONCLUSIONS: n-3 PUFA decreased several markers of NAFLD; however, there was a lower observed efficacy in NASH treatment. Further long-term placebo-controlled studies with adequate power and supplementation duration and standardized and sensitive detection methods are needed to determine the efficacy of EPA and DHA individually and in a mixture to treat NAFLD and NASH.