The extrapancreatic effects of the sulfonylurea drug glyburide in insulin-dependent diabetes mellitus were examined in a double-blind, prospective study involving 28 patients. Administration of glyburide in addition to the usual diet and insulin dose for 6 mo led to a minimal and transient decrease in hemoglobin A1c and total glycosylated hemoglobin. Insulin receptors of peripheral monocytes were initially normal in both number and affinity in this group of insulin-dependent diabetic patients, but, after 6 mo of glyburide therapy, binding to insulin receptors declined at the lower insulin concentration range without falling out of the normal range. No changes could be demonstrated in plasma triglycerides, cholesterol, or lipoprotein-cholesterol fractions. We conclude that the extrapancreatic effects of the sulfonylurea glyburide in insulin-deficient diabetic subjects are small. These effects may be mediated through a postinsulin receptor mechanism.