To evaluate the effect of genetic background on oxygen (O2) toxicity, nine genetically diverse mouse strains (129/SvIm, A/J, BALB/cJ, BTBR+(T)/tf/tf, CAST/Ei, C3H/HeJ, C57BL/6J, DBA/2J, and FVB/NJ) were exposed to more than 99% O2 for 72 h. Immediately following the hyperoxic challenge, the mouse strains demonstrated distinct pathophysiologic responses. The BALB/cJ and CAST/Ei strains, which were the only strains to demonstrate mortality from the hyperoxic challenges, were also the only strains to display significant neutrophil infiltration into their lower respiratory tract. In addition, the O2-challenged BALB/cJ and CAST/Ei mice were among six strains (A/J, BALB/cJ, CAST/Ei, BTBR+(T)/tf/tf, DBA/2J, and C3H/HeJ) that had significantly increased interleukin 6 concentrations in the whole lung lavage fluid and were among all but one strain that had large increases in lung permeability compared with air-exposed controls. In contrast, the DBA/2J strain was the only strain not to have any significant alterations in lung permeability following hyperoxic challenge. The expression of the extracellular matrix proteins, including collagens I, III, and IV, fibronectin I, and tenascin C, also varied markedly among the mouse strains, as did the activities of total superoxide dismutase (SOD) and manganese-SOD (Mn-SOD or SOD2). These data suggest that the response to O2 depends, in part, on the genetic background and that some of the strains analyzed can be used to identify specific loci and genes underlying the response to O2.