Although polycythemia commonly occurs in hypoxic patients, most hemodynamic studies of polycythemia have been done in the normoxemic state. We studied the combined effects of polycythemia and hypoxia. In 11 splenectomized, anesthetized dogs, hematocrit was increased from 42.6 ± 1.2 to 65.5 ± 0.6% (SEM) by isovolumic exchange transfusions with fresh canine packed RBC's. Studies were conducted during normoxia (Pao2 = 113.8 ± 4.2 mm Hg) and hypoxia (Pao2 = 40.5 ± 1.6 mm Hg). Polycythemia alone increased pulmonary vascular resistance by 112 ± 4.6% (P < 0.01) and hypoxia alone increased pulmonary vascular resistance by 141 ± 11.4% (P < 0.01). Combined hypoxia and polycythemia increased pulmonary vascular resistance by 308 ± 28.1% (P< 0.005), an effect significantly greater than that of hypoxia or polycythemia alone (P< 0.005). In contrast, systemic vascular resistance increased with polycythemia by 90 ± 8.8% (P < 0.01), whereas hypoxia had no effect on systemic vascular resistance either alone or when combined with polycythemia. Polycythemia decreased cardiac output by 50 ± 1.8% (P < 0.01), whereas hypoxia had no significant effect alone or when combined with polycythemia. Oxygen transport was decreased by polycythemia by 29 ± 0.8% (P < 0.01) due to decreased cardiac output. Hypoxia decreased oxygen transport by 28 ± 0.9% (P< 0.01) due to a decrease in arterial oxygen content. Combined hypoxia and polycythemia decreased oxygen transport by 50 ± 2.6% (P < 0.01) an effect greater than that of hypoxia or polycythemia alone. In four control dogs, exchange with whole blood produced no change in the variables studied. Synergistic effects of hypoxia and polycythemia on pulmonary vascular resistance reflect combined influences of increased blood viscosity and hypoxic pulmonary vasoconstriction. Such a combination may contribute to the occurrence of cor pulmonale in patients with hypoxia and secondary polycythemia.