OBJECTIVE To study the outcome of a modified oral desensitization protocol for trimethoprim-sulfamethoxazole in human immunodeficiency virus infected patients with Pneumocystis carinii pneumonia and acquired immune deficiency syndrome. METHODS A prospective study. METHODS Tertiary care referral center. METHODS Thirteen human immunodeficiency virus infected patients with Pneumocystis carinii pneumonia and allergy to sulfonamides who failed alternative therapy. METHODS Oral desensitization to trimethoprim-sulfamethoxazole. METHODS Nature of allergic reactions, toxicity of alternate medications, indication as well as outcome of trimethoprim-sulfamethoxazole desensitization and routine laboratory determinations. RESULTS The most common reaction to trimethoprim-sulfamethoxazole was generalized, pruritic maculopapular rash (n = 10, 76.9%) followed by urticaria/angioedema in two patients (15.38%). Two patients had generalized pruritus without rash. All patients (n = 13) tolerated oral desensitization to trimethoprim-sulfamethoxazole without any adverse reactions including three patients who were critically ill and on mechanical ventilation. Thus the success rate of our protocol was 100%. No patient had received antihistamines prior to or during the protocol. Four patients (5, 6, 7, and 9) were receiving prednisone for severe Pneumocystis carinii pneumonia. Total followup has ranged from 4 to 84 weeks. Two patients died during followup due to causes unrelated to desensitization. All other patients are tolerating trimethoprim-sulfamethoxazole without any allergic reactions. CONCLUSIONS Oral desensitization to trimethoprim-sulfamethoxazole, as per this protocol is safe, in that there were no systemic or cutaneous reactions during desensitization as well as followup. It is well tolerated in all patients, including the three critically ill patients. As judged by the outcome and ability to tolerate trimethoprim-sulfamethoxazole after desensitization, the procedure is successful in all patients in this study. Equipped with this protocol one can evaluate possible mechanisms of desensitization such as oral tolerance or mediator depletion in a controlled fashion.