We conducted a prospective, randomized clinical trial over a two-year period in patients with acute lymphocytic leukemia to assess the effectiveness of trimethoprim-sulfamethoxazole given on three consecutive days each week as compared with daily in the prevention of Pneumocystis carinii pneumonitis. P. carinii pneumonitis did not develop in any of 92 patients receiving the drug daily (30,602 patient-days) or in any of 74 who received it three consecutive days a week (27,329 patient-days), whereas the incidence of the infection expected without prophylaxis is 21 percent. One patient, excluded from both groups because of an adverse reaction to sulfonamides in the past, acquired P. carinii pneumonitis. Especially noteworthy was a difference in the occurrence of systemic mycoses, with 10 cases in the daily-treatment group and only 1 case in the three-days-a-week group (P = 0.024). No differences were observed in the rates of other infections or adverse effects associated with the drug. We conclude that trimethoprim-sulfamethoxazole is as effective given three days a week as it is given daily in the prevention of P. carinii pneumonitis and that the intermittent schedule has the advantages of less frequent fungal infections and lower cost. Intermittent chemoprophylaxis may be especially beneficial to certain patients who are unable to tolerate the daily doses.