Drug-induced crystalluria is a cause of acute renal failure that has not to be overlooked. Especially sulfonamides are known to be little solubles in acidic urine. Among these drugs, sulfadiazine produces the so-called shocks of wheat crystals, whose formation can be avoided by opportune hydration and alkalinization of the patient. Sulfamethoxazole is another drug of this class that has seldom been reported to cause a pleomorphic crystalluria. We report the case of two patients treated with sulfamethoxazole who developed a crystalluria that is very similar to the sulfadiazine one. Sulfamethoxazole is widely used in clinical practice in association with trimethoprim and it is known to cause acute renal failure, although little is known about the pathogenesis of this nephrotoxicity. Our cases, along with the cases previously reported, may suggest that sulphamethoxazole can act as a nephrotoxic agent through crystals production. Notably, in our cases, discontinuation of the drug led to disappearance of the crystals.