When given in standard dosages to treat bacterial respiratory and urinary tract infections, trimethoprim-sulfamethoxazole (TMP-SMX) is not commonly associated with hyperkalemia. However, the emergence of the acquired immunodeficiency syndrome has led to increased numbers of patients with Pneumocystis carinii pneumonia (PCP) who require high-dose TMP-SMX therapy. A 25-year-old man with human immunodeficiency virus infection developed hyperkalemia while receiving high-dose TMP-SMX for PCP. His baseline serum potassium of 3.0 mEq/L, which increased to 4.2 mEq/L after potassium replacement therapy, rose to 6.9 mEq/L after 8 days of TMP-SMX. No other etiology was found for the hyperkalemia, and the disorder resolved when TMP-SMX was stopped. It recurred when the patient was rechallenged with high doses of TMP-SMX during a second treatment course for PCP. This case and a review of previous reports highlight the importance of monitoring serum potassium concentrations in patients receiving high-dose TMP-SMX.