BACKGROUND Hypersensitivity reactions to trimethoprim-sulfamethoxazole (TMP-SMX) are very common in HIV-infected patients, leading to drug discontinuation. However, it is the drug of choice as prophylaxis for Pneumocystis carinii pneumonia. OBJECTIVE We sought to determine the safety and long-term efficacy of a 6-hour TMP-SMX-graded challenge in a group of hypersensitive HIV-infected patients. METHODS Forty-four consecutive HIV-infected patients with documented TMP-SMX hypersensitivity were seen in our outpatient allergy department. They ingested 12 doses of increasing amounts of TMP-SMX at half-hour intervals. Thereafter, they took 80/400 mg TMP-SMX daily and were advised to "treat through" every nonbullous cutaneous adverse reaction. RESULTS All 44 patients tolerated the procedure without any adverse reactions during the day of challenge. Eleven of the 44 patients experienced mild hypersensitivity reactions on days 1 to 2 (8 patients) and 8 to 10 (3 patients), consisting mainly on a 1-day pruritic maculopapular eruption. Two patients stopped TMP-SMX at day 1, and 2 stopped it at days 10 and 15, giving an overall success rate at 1 month of 91% (40 of 44). Two were successfully rechallenged late. After a median follow-up of 10 months, 42 patients were taking TMP-SMX without any adverse reaction, giving an overall success rate of 95%. CONCLUSIONS A 6-hour graded challenge with cautious "treating through" of mild reactions enables more patients to take TMP-SMX and is safe and effective.