Goiter and hypothyroidism have been reported as side effects of sulfonylurea therapy. To test the effects of glyburide, a new generation sulfonylurea drug, on thyroid function, we studied 15 male Type 2 diabetic patients before and after 6 weeks of treatment with this drug, and we repeated the studies on 9 of these patients who remained on the drug for at least 24 weeks. All hypoglycemic agents were discontinued for 1 week before the study. Patients had a baseline thyroid examination, serum T4, free T4 index (FT4I), T3, and free T3 index (FT3I), fasting serum glucose (FSG), HbA1c and a TRH test of TSH reserve. The dose of glyburide was adjusted at 2 weeks, and the tests were repeated after 6 weeks and after at least 24 (24-32) weeks of glyburide therapy. Compared to baseline, there was a significant decrease in FSG at 6 weeks and again at 24-32 weeks. Body weight, thyroid size, serum FT4I, FT3I, and TSH did not change significantly. After 6 weeks of therapy, there was no significant correlation of FSG or HbA1c with FT4I, FT3I, basal or peak TSH or TSH response area. The integrated area under the TSH response curve decreased significantly in 8 patients at 24 weeks (p less than 0.05). There was a positive correlation between FSG and the area under the TSH response curve using the combined baseline and 24 week data in these patients (r = 0.73, p less than 0.01). In this study with patients acting as their own controls, there was no effect of glyburide on thyroid function or size.