Suppression of nocturnal hepatic glucose production is key in the treatment of noninsulin-dependent diabetes mellitus (NIDDM). In this article, the authors compare the effectiveness of dosing glyburide at bedtime versus in the morning on glycemic control in patients with NIDDM under suboptimal control. In a placebo-controlled, double-blind crossover trial, 32 patients with NIDDM with suboptimal control on chronic glyburide treatment fulfilling entry criteria were randomized to receive one of two regimens: (1) glyburide at bedtime and placebo in morning or (2) placebo at bedtime and glyburide in the morning. After 6 months of a regimen, patients crossed over to the other treatment and completed an additional 6-month period. After baseline assessment, fasting blood sugar, history, physical exam, and compliance assessments were performed monthly. HbA1c was measured bimonthly and Sustacal tolerance tests were performed at the end of each 6-month treatment period. During the initial 6-month comparison fasting, blood sugar concentration decreased 5% in bedtime ingesters and rose 10% in the morning patients. These changes were not statistically significant. HbA1c decreased significantly in the morning group but remained unchanged in the bedtime group. At the end of 12 months, nighttime dosing resulted in better home glucose monitoring values, fasting blood sugar results, and Sustacal tolerance profiles, but the differences were not statistically significant. No hypoglycemia was observed in the monitored data collected. Bedtime dosing of glyburide resulted in measurable improvement in fasting blood sugar and carbohydrate tolerance curves, but not to a degree justifying general recommendation of this technique in patients with NIDDM with secondary failure to oral agents.