We investigated the effect of high VT ventilation on adult and newborn rats by examining pulmonary injury and cytokine messenger RNA (mRNA). On the basis of compliance, edema formation, and histology, ventilation with 25 ml.kg(-1) was more injurious to adult rats than newborns. Ventilation with 40 ml kg(-1) minimally affected compliance in newborns but caused death in adults. Ventilation of adults for 30 minutes at 25 ml kg(-1) upregulated the mRNA expression of interleukin (IL)-1beta, IL-6, tumor necrosis factor-alpha (TNF-alpha), macrophage inflammatory protein-2 (MIP-2), and IL-10, whereas in newborns such ventilation only increased mRNA expression of MIP-2 and IL-10. When VT was raised to 40 ml kg(-1) in newborns, IL-1beta mRNA levels were additionally increased at 30 minutes, whereas ventilation for 3 hours additionally increased IL-6 and TNF-alpha mRNA. In newborns, the addition of 100% oxygen (O2) to 30 minutes of ventilation blunted the high VT induction of IL-1beta, IL-10, and MIP-2 mRNA expressions, whereas at 3 hours, 100% O2 concentration synergistically increased the mRNAs for TNF-alpha and IL-6. Overall, adult rats are more susceptible to high VT-induced lung injury compared with newborns. In newborns, the inflammatory response is dependent on VT, duration, and supplemental O2. Thus, recommendations for VT limitation based on adult data may be inappropriate for newborns.