We present a study in which we investigated the safety of therapeutic mild hypothermia on the neonatal cardiovascular system. In an attempt to mimic the state of affairs that may follow an hypoxic-ischemic insult, the effect of moderate hypothermia was studied under conditions where cardiovascular integrity was impaired. Newborn piglets where randomized to either receive a thromboxane A₂ mimetic or an hypoxic inspiratory gas mixture. Periods of hypothermia (5 °C below normothermic level) preceded or were combined with those agents in a random manner. Isolated hypothermia decreased cardiac output by 25%, and increased pulmonary vascular resistance by 48%. Mesenteric blood flow and cerebral blood flow decreased by a similar magnitude (21 and 18% respectively). When hypothermia was combined with alveolar hypoxia or thromboxane, the increase in pulmonary vascular resistance (103 and 292% respectively) exceeded the increase produced by the sum of each individual component. In contrast neither hypoxia nor thromboxane potentiates the hypothermia induced decrease in mesenteric blood flow. Ileal mucosal blood flow remained stable for all conditions. We conclude that mild therapeutic hypothermia may be safe in conditions where cardiac function is impaired, but may be more hazardous when severe pulmonary hypertension is present.