Sildenafil, an oral phosphodiesterase type-5 inhibitor, has vasodilatory effects through a cyclic guanosine 3', 5'-monophosphate-dependent mechanism, whereas beraprost, an oral prostacyclin analog, induces vasorelaxation through a cAMP-dependent mechanism. We investigated whether the combination of oral sildenafil and beraprost is superior to each drug alone in the treatment of pulmonary hypertension. Rats were randomized to receive repeated administration of saline, sildenafil, beraprost, or both of these drugs twice a day for 3 weeks. Three weeks after monocrotaline (MCT) injection, there was significant development of pulmonary hypertension. The increases in right ventricular systolic pressure and ratio of right ventricular weight to body weight were significantly attenuated in the Sildenafil and Beraprost groups. Combination therapy with sildenafil and beraprost had additive effects on increases in plasma cAMP and cyclic guanosine 3', 5'-monophosphate levels, resulting in further improvement in pulmonary hemodynamics compared with treatment with each drug alone. Unlike MCT rats given saline, sildenafil, or beraprost alone, all rats treated with both drugs remained alive during 6-week follow-up. These results suggest that combination therapy with oral sildenafil and beraprost attenuates the development of MCT-induced pulmonary hypertension compared with treatment with each drug alone.