The effect of sulindac and tolbutamide on the control of diabetes was studied in 12 tolbutamide-treated maturity-onset diabetics with stable glycemic control. After one week of hospitalization on a metabolic ward for adjustment of diet and activity, the patients were treated with sulindac, 200 mg twice daily for one week. The time-to-peak plasma tolbutamide concentration was 3.1, 3.1, and 3.2 hr, respectively, after tolbutamide alone, after the first dose of sulindac, and after sulindac for a week. The areas under the plasma tolbutamide curve were 23.68, 22.10, and 22.78 for the same periods. The half-life for plasma tolbutamide was 7.46, 7.15, and 7.38 hr, respectively. None of the differences were statistically significant. The mean fasting plasma sugar was lower after the sulindac treatment (from 12.5 to 112.9 mg/100 ml, p less than 0.05), but the postprandial values increased slightly (from 137.7 to 142.6). It was concluded that there was no clinically significant interaction between sulindac and tolbutamide.