Supplementation of omega-3 fish oils (n-3 FO) usually worsens the glycemic control in type 2 diabetic subjects. This may be a dose-related phenomenon and is reversed after discontinuation of the n-3 FO supplementation. An increase in the daily caloric intake, due to the fat content of n-3 FO supplements, and a consequent weight gain may contribute to the increase in hyperglycemia. Mechanisms of the increase in hyperglycemia include: (1) n-3 FO may interfere with insulin secretion from the pancreas, and this in turn can cause an increase in the hepatic glucose output and/or a decrease in the glucose uptake by the peripheral tissues; (2) n-3 FO may primarily decrease the sensitivity of liver to insulin action and consequently increase gluconeogenesis and/or glycogenolysis and/or decrease the glycogenesis; (3) n-3 FO may primarily affect the sensitivity of peripheral tissues to insulin, resulting in decreased glucose-uptake; (4) n-3 FO may increase the availability of gluconeogenic substrates by directly altering the partitioning of the metabolic fuels for different pathways in the liver. [formula: see text] Direct experimental testing of these possibilities has been difficult, because n-3 FO affects the carbohydrate metabolism differently in animal models than in humans. The available data suggest that n-3 FO inhibits insulin secretion in response to glucose load, mixed meal, and glucagon but not at the fasting state. Hepatic glucose output is increased. Sensitivity of the peripheral tissues to insulin is not changed. An encouraging observation is that the hyperglycemic effect of n-3 FO may decrease with time even when therapy is continued. Proper use of this treatment modality requires careful evaluation of the risk/benefit ratio for every individual patient.