Hypoglycemia resulting from the combination of sulfonylurea and sulfonamides is a recognized drug interaction. Hypoglycemia induced by sulfonamides alone may be encountered less frequently. Because of their structural similarities to sulfonylureas, sulfonamides are liable to facilitate hypoglycemia by increasing insulin release in susceptible individuals. Sulfonamides can potentiate the hypoglycemic effect of sulfonylurea agents when given in combination. We describe a malnourished patient with severe infection who developed hypoglycemia during high-dose trimethoprim/sulfamethoxazole therapy. Elevated C-peptide concentrations during the hypoglycemic episode indicate that hypoglycemia resulted from increased endogenous insulin secretion. As malnourished patients are prone to hypoglycemia, we suggest that they should be monitored carefully if they are on sulfonamide therapy.