We investigated the possibility of a drug interaction between the antilipemic agent halofenate and sulfonylureas. Twelve young, healthy men were given 1 g of tolbutamide by mouth before and after 12 days of double-blind treatment with 1 g per day of halofenate, or placebo. There was a significant increase in serum tolbutamide at eight, 10 and 12 hours (P less than 0.01) and a significant (P less than 0.01) decrease in serum glucose at one, four and six hours after halofenate treatment, but not after placebo. In a long-term, double-blind study of halofenate or clofibrate treatment of patients with Type IV hyperlipoproteinemia, diabetic patients receiving a sulfonylurea and halofenate either required a reduction in the dose of the sulfonylurea or demonstrated significantly improved control of hyperglycemia (P less than 0.05) or both. No appreciable decrease in serum glucose levels was noted in diabetic patients receiving sulfonylurea and clofibrate. This interaction between halofenate and sulfonylureas is clinically important, especially in view of the association of hyperlipemia and diabetes.