A 45-year-old man underwent renal transplant for end-stage renal disease complicating systemic lupus erythematosis. Within 24 hours of initiating Pneumocystis carinii pneumonia (PCP) prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX) he developed fever and confusion. Cerebrospinal fluid examination revealed a pleocytosis but cultures were negative. The patient improved within three days after cessation of the TMP-SMX but symptoms recurred rapidly upon drug rechallenge. Drug-induced aseptic meningitis is an uncommon but well described clinical entity. This is the first case described in a patient following renal transplantation. The literature is reviewed and the clinical features, diagnostic challenges and possible mechanisms of TMP-SMX-induced aseptic meningitis are discussed. This problem may be more common in the transplant population than is recognized given the difficulty of diagnosis combined with the widespread use of TMP-SMX as PCP prophylaxis.