Adverse drug reactions to the sulfonamide antibiotics are uncommon. When they do occur, they usually manifest as a rash or urticaria. Our review of the recent literature found that while sialadenitis is listed as a possible side effect of sulfonamide use, no actual case has ever been reported until now. We describe a case of acute bilateral parotitis that arose as a side effect of sulfonamide antibiotic treatment. We also examine the relevance of such pathology to the proposed mechanisms of sialadenitis, and we briefly discuss sulfonamide-induced pancreatitis. Lastly, we review the controversy over the possibility that some adverse drug reactions may be caused by cross-reactivity among different classes of sulfonamides.