No consensus exists as to the best approach for treating markedly symptomatic patients with new-onset (or diet-treated) type 2 diabetes. Therefore, based on the experience of one successful case, further studies were undertaken to determine the safety and efficacy of maximal dose glyburide (10 mg, twice daily, in patients < 65 yr of age) or half the dose (10 mg, daily, in patients > or = 65 yr of age) for treating these patients. Fifty-five patients with polyuria, polydipsia, nocturia, involuntary weight loss, and blood glucose concentrations of 300 mg/dL or greater were treated following protocols that used maximal dose ( < 65 yr of age) or half-maximal dose ( > or = 65 yr of age) sulfonylurea agent therapy. Data were collected retrospectively in 30 patients and prospectively in 25. Patients in the prospective group differed only in that more laboratory measurements were obtained, and less strict guidelines for using insulin were adopted. Data were collected in both groups at baseline and 1 week and 4 months after starting the sulfonylurea agent therapy. Patients responded rapidly with a fall in blood glucose levels from 456 +/- 12 mg/dL at baseline to 202 +/- 10 mg/dL at 1 week to 120 +/- 5 mg/dL at 4 months. Glycated hemoglobin levels fell from 18.1 +/- 0.4% at baseline to 8.1 +/- 0.2% ( P < 0.0001) at 4 months. Most patients had symptomatic improvement within 3 days. Seventeen patients had positive (small or larger) urinary ketones, and 5 had positive serum ketones. Insulin to glucose and C peptide to glucose ratios improved maximally at 1 week, indicating rapid reversal of glucotoxicity on the beta-cell. At 4 months, 11 patients were receiving diet therapy alone, 29 were receiving submaximal dose sulfonylurea agent therapy, 6 remained on maximal dose sulfonylurea agent therapy, and only 3 were receiving insulin therapy. Six patients were lost to follow-up. No patient experienced hypoglycemia in the first 2 weeks of treatment. Maximal dose sulfonylurea agent therapy is a safe and effective method for treating patients with markedly symptomatic type 2 diabetes. Patients improve rapidly and are able to avoid the immediate institution of long term insulin therapy.