Sulfonamides have been reported to augment the hypoglycemic effects of chlorpropamide, glyburide, and tolbutamide. This case report is the first to describe a possible interaction with glipizide. An 83-year-old man receiving glipizide 10 mg bid developed symptomatic hypoglycemia within three days of adding trimethoprim/sulfamethoxazole (TMP/SMX) to his regimen. All other factors, including laboratory data, dietary intake, activity level, and concurrent use of other medications, were stable and noncontributory. This patient may have been at increased risk for this interaction secondary to his age and history of alcohol abuse. The mechanism of the interaction is probably inhibition of glipizide metabolism rather than protein-binding displacement. This case suggests that, when TMP/SMX is combined with glipizide, patients should be closely monitored, especially those at high risk for hypoglycemia.