Treatment with either pentamidine isethionate or trimethoprim-sulfamethoxazole significantly reduces the mortality of Pneumocystis carinii pneumonia. It is not known whether a combination might act in an additive, synergistic, or antagonistic manner. We studied the interaction of these two agents in the steroid-conditioned rat model of pneumocystosis. Of animals receiving pentamidine alone, 48% died and 45% had P. carinii cysts at autopsy. Trimethoprimsulfamethoxazole alone resulted in 21% mortality, and cysts were found in 28%. Both agents in full doses resulted in 45% deaths and cysts in 37%. Animals treated with half-dosages of pentamidine plus trimethroprim-sulfamethoxazole had mortality of 35%, and 21% had cysts. Trimethoprim alone, in two dosages, was ineffective in eradicating P. carinii cysts. The data suggest that combination therapy is no more effective than trimethoprim-sulfamethoxazole alone in the treatment of P. carinii pneumonia.