In some infants, administration of surfactant has been associated with an acute decrease in blood pressure. We hypothesized that independent of patent ductus arteriosus, low blood volume sensitizes to a negative hemodynamic response to surfaetant supplementation. Respiratory failure was induced by bronchoalveolar lavage (BAL) in 30 young rabbits that were paralyzed and ventilated using tidal volumes of 10 ml/kg. After BAL, 15 ml/kg blood was withdrawn while the same volume of one of the following was infused: Ringer's lactate (n = 12); 5% albumin (n = 5); or leukocyte-free red blood cells (RBC, n = 6). The controls were not phlebotomized (n = 7). After blood withdrawal and transfusion, natural surfactant was given (100 mg/kg). The blood volume and pulmonary capillary leak were calculated. Cardiac output (CO) and vascular resistances were measured (Ringer's lactate; n = 5; controls, n = 4). Blood withdrawal and replacement had no immediate effect on either lung function or hemodynamics. Suffactant supplementation improved the gas exchange in all but the albumin-treated animals that had increased protein concentration in epithelial lining fluid. In the Ringer's lactate group, there was a 35% decrease (p < 0.05) in blood pressure, a 28% decrease (p < 0.05) in CO, and a 54% increase (p < 0.05) in pulmonary vascular resistance, shortly after surfactant administration. In the other groups, there was either a transient (controls) or no (RBC and albumin groups) decrease in blood pressure. The total blood volume and the intrapulmonary blood volume were lower in the Ringer's lactate group than in the RBC group. According to the present results, blood pressure and CO may decrease acutely when exogenous surfactant is administered coincidental with blood loss.