Coagulopathy and alveolar fibrin deposition are common in sick neonates and attributed to the primary disease, as opposed to their ventilatory support. Hypothesizing that high tidal volume ventilation activates the extrinsic coagulation pathway, we air ventilated newborn and adult rats at low (10 ml/kg) or high (30 ml/kg) tidal volume and compared them with age-matched nonventilated controls. Blood was collected at the end of the experiment for measurement of clot time, tissue factor, and other coagulation factor content. Similar measurements were obtained from lung lavage material. The newborn clot time (44 ± 1) was lower and plasma tissue factor content higher (103.4 ± 0.4) than adults (88 ± 4 s and 26.6 ± 1.4 units; P < 0.01). High, but not low, tidal volume ventilation of newborns for as little as 15 min significantly reduced clot time and increased plasma tissue factor content ( P < 0.01). High volume ventilation increased plasma factor Xa (0.1 ± 0.1 to 1.6 ± 0.4 nM; P < 0.01) and thrombin (1.3 ± 0.2 to 2.2 ± 0.4 nM; P < 0.05) and decreased antithrombin (0.12 ± 0.01 to 0.05 ± 0.01; P < 0.01) in the newborn. Lung lavage material of high volume-ventilated newborns showed increased ( P < 0.01) factor Xa and thrombin. No changes in these parameters were observed in adult rats that were high volume ventilated for up to 90 min. Compared with adults, newborn rats have a greater propensity for volutrauma-activated intravascular coagulation. These data suggest that mechanical ventilation promotes neonatal thrombosis via lung tissue factor release.