During strenuous exercise in sheep, lung lymph flow increases within seconds and rises to levels 7- to 10-fold over baseline. Concomitant with the flow increase, the lymph protein content rapidly decreases to levels consistent with severe capillary hypertension. This pattern of clearance of filtered fluid is quite different than is seen with the passive capillary hypertension that results from mechanical obstruction of the mitral valve. In passive capillary hypertension, the increase in lymph flow and reduction in lymph protein content develop over several hours. The purpose of this study was to discover if these observed differences in edema clearance are related to the hyperpnea that accompanies exercise. Sheep were instrumented for continuous measurement of pulmonary arterial, left atrial, and systemic pressures, cardiac output by ultrasound, lung lymph flow, and ventilation. First, hemodynamics, ventilatory, and lymph clearance variables were measured during moderate exercise at 2.8 mph on a treadmill. Second, on a separate occasion, sheep were induced to hyperventilate to the same minute ventilation as during exercise, using modest CO2 stimulation. Lymph flow and hemodynamics were unaffected by this hyperpnea. The third arm of the experiment was to raise pulmonary microvascular pressure at rest to the level seen with exercise by means of a balloon catheter placed in the mitral valve. Lymph flow rose and protein content decreased slowly and to a lower degree than seen with exercise despite a comparable microvascular pressure. Finally, left atrial hypertension and induced hyperpnea were combined in sheep at rest, and the resulting lymph flow and protein content were the same as seen with exercise at similar pressures and ventilation. We conclude that hyperpnea is a major mechanism of interstitial liquid clearance during exercise, and may be largely responsible for preventing pulmonary edema that might occur at the high microvascular pressures of strenuous exercise.