To evaluate the efficacy of primary prophylaxis for Pneumocystis jiroveci pneumonia (PCP) in patients with connective tissue disease (CTD) and immunosuppression, we compared trimethoprim-sulfamethoxazole (TMP-SMZ) with aerosolized pentamidine. Forty-eight CTD patients of Kitasato University Hospital whose CD4+ lymphocyte count in the peripheral blood was less than 300 microl(-1) were reviewed from 2002 to 2004. Twenty-seven patients received TMP-SMZ and none of them developed PCP. Among 18 patients receiving aerosolized pentamidine, three patients developed PCP. These data indicate that TMP-SMZ is better for prophylaxis than aerosolized pentamidine.