The metabolic effects of a 3-week dietary supplement of a fish oil concentrate was examined in mildly obese, normotriglyceridemic men with non-insulin-dependent diabetes mellitus (NIDDM) treated with hypoglycemic agents (n = 20). Patients were randomized into two groups, receiving 15 ml per day of fish oil (Martens Oil, Norway) containing 3.1 g of omega-3 fatty acids (FA) (n = 10) or placebo (n = 10). Whereas fish oil led to the expected increase in the ratio of omega-3 to omega-6 FA in serum phospholipids, reflecting the increase in omega-3 FA intake, it did not alter fasting or mixed meal stimulated blood glucose, plasma insulin, and C-peptide concentrations. No changes in insulin action were noted, estimated by the metabolic clearance rates of glucose at plasma insulin levels of approximately 100 microU/ml and 1,400 microU/ml during a hyperinsulinemic, isoglycemic clamp; no changes were seen in insulin binding to erythrocytes. We conclude that during short-term administration, no adverse effects of low dose fish oil on glucose homeostasis were found in mildly obese NIDDM patients treated with oral hypoglycemic agents.