BACKGROUND: COPD, the fifth-leading cause of death worldwide, is characterized by chronic inflammation. However, no available agent can effectively cure this inflammation. A dietary supplement containing omega-3 polyunsaturated fatty acids (PUFAs) has anti-inflammatory effects. In this study, we hypothesized that nutritional support with omega-3 PUFA-rich diets may be useful for treating COPD, and we compared the clinical features and inflammatory mediator levels between the COPD patients who received an omega-3 PUFA-rich supplement and those who received a nonrich supplement. METHODS: Sixty-four COPD patients received 400 kilocalories per day of an omega-3 PUFA-rich supplement (n-3 group) or an omega-3 PUFA-nonrich supplement (n-6 group) for 2 years. We prospectively investigated the clinical features of these patients and measured the levels of inflammatory mediators. RESULTS: In 6-min walk testing, the dyspnea Borg scale and decrease of arterial oxygen saturation measured by pulse oximetry significantly improved in the n-3 group. Leukotriene B4 levels in serum and sputum and tumor necrosis factor-alpha and interleukin-8 levels in sputum decreased significantly in the n-3 group, while there was no significant change in the n-6 group. Two patients in the n-3 group and three patients in the n-6 group had mild diarrhea, and three patients in the n-3 group and three patients in the n-6 group had nausea; however, their symptoms were controllable and they improved with treatment. With multiple regression analysis, it was proved that the omega-3 PUFA-rich diet significantly contributed to the change in cytokine levels in this study. CONCLUSION: We suggest nutritional support with an omega-3 PUFA-rich diet as a safe and practical method for treating COPD.