Overexpression of IL-6 markedly diminishes hyperoxic lung injury, hyperoxia-induced cell death, DNA fragmentation, and enhances Bcl-2 expression. We hypothesized that changes in the interactions between Bcl-2 family members play an important role in the IL-6 mediated protective response to oxidative stress. Consistent with this hypothesis, we found that IL-6 induced Bcl-2 expression both in vivo and in vitro, disrupted interactions between pro-apoptotic and anti-apoptotic factors, and suppressed H2O2 induced loss of mitochondrial membrane potential in vitro. In addition, IL-6 overexpression in mice protects against hyperoxia induced lung mitochondrial damage. The over-expression of Bcl-2 in vivo prolonged the survival of mice exposed to hyperoxia and inhibited alveolar-capillary protein leakage. In addition, apoptosis associated DNA fragmentation was substantially reduced in these animals. This IL-6 mediated protection was lost when Bcl-2 was silenced, demonstrating that Bcl-2 is an essential mediator of IL-6 cytoprotection. Finally, Bcl-2 blocked the dissociation of BAK from mitofusion protein 2 (Mfn2), and inhibit the interaction between BAK and Mfn1. Taken together, our results suggest that IL-6 induces Bcl-2 expression to perform cytoprotective functions in response to oxygen toxicity, and that this effect is mediated by alterations in the interactions between BAK and mitofusion proteins.