Morbidity and mortality associated with acute lung injury (ALI) and acute respiratory distress syndrome remain substantial. Though many candidate genes have been tested, a clear understanding of the pathogenesis is lacking, as is our ability to predict individual outcome. Because ALI is a complex disease, single gene approaches cannot easily identify effectors that must be treated concurrently. We have employed a strategy to help identify critical genes and gene combinations involved in ALI mortality. Using hyperoxia to induce ALI, a mouse model for genetic analyses of ALI survival time was identified; C57BL/6J (B) mice are sensitive (i.e. die early), whereas 129X1/SvJ (S) mice are significantly more resistant, but with low penetrance. Segregation analysis of reciprocal F₂ mice generated from B and S strains revealed significant sex, cross, and parent-of-origin effects. Quantitative trait locus (QTL) analysis identified 5 chromosomal regions significantly linked to hyperoxic ALI (HALI) survival time (named Shali1 to Shali5). Further analyses demonstrated that both parental strains contribute resistance alleles to their offspring and that the phenotype demonstrated parent-of-origin effects. To validate earlier findings, we generated and tested mice from all 8 possible B-S derived backcrosses. Results from segregation and QTL analyses of 935 backcrosses, alone and combined with the previous 840 B-S derived F₂ population, further supported the highly significant QTLs on chromosomes 1 (Shali1) and 4 (Shali2), and confirmed that sex, cross, and the parent-of-origin all contribute to survival time with HALI.