Increased interest in using omega-3 fatty acids led us to examine their metabolic effects in six men with type II (non-insulin-dependent) diabetes mellitus. After 1 month of a diet supplemented with these fatty acids, the patients' fasting glucose rose from 13.1 +/- 1.3 to 15.3 +/- 1.3 mmol/L (P = 0.03) and glucose area during a mixed meal profile rose by 22% (P = 0.04). Basal hepatic glucose output rose from 97 +/- 9 to 122 +/- 8 mg/m2 . min (P = 0.004) but glucose disposal rates measured by euglycemic glucose clamp were unchanged. Fasting insulin levels were similar; peak insulin levels stimulated by meals or intravenous glucagon fell by 30% and 39%, respectively. Plasma and erythrocyte content of omega-3 fatty acid rose significantly. After omega-3 fatty acid withdrawal, fasting glucose returned to baseline. Omega-3 fatty acid treatment in type II diabetes leads to rapid but reversible metabolic deterioration, with elevated basal hepatic glucose output and impaired insulin secretion but unchanged glucose disposal rates. Caution should be used when recommending omega-3 fatty acids in type II diabetic persons.