Acute lung injury (ALI) and its most severe presentation, acute respiratory distress syndrome, represent a full spectrum of a complex and devastating illness, with associated mortality that still hovers around 30–40%. Even supplemental O2, a routine and necessary therapy for such patients, paradoxically causes lung injury. The detrimental effects of O2 have established hyperoxic ALI (HALI) as a conventional model to study neonatal and adult forms of respiratory distress syndromes in experimental animals. To confront the high ALI mortality problem quite differently, we recently identified a mouse model (sensitive C57BL/6J and resistant 129X1/SvJ mice) to assess the genetic complexity of HALI and to identify genes affecting strain survival differences. Segregation analysis of 840 F2 mice generated from all four possible intercrosses between C57BL/6J and 129X1/SvJ mice demonstrated that survival time is a quantitative trait with decreased penetrance, and significant sex, cross, and parent-of-origin effects. Quantitative trait locus (QTL) analyses of the total F2 population identified three highly significant (named Shali1, Shali2 and Shali3, for Survival to hyperoxic acute lung injury) and one significant ( Shali4) linkage. Analysis of F2 subpopulations further identified a male-specific QTL ( Shali5). QTL allelic comparisons supported cross and sex effects and were consistent with imprinting. Genome-wide pairwise analysis predicted additive gene-gene interactions between the QTLs and also revealed a significant epistatic interaction with an otherwise unlinked region. QTL results confirmed that both parental strains contribute dominant resistance alleles to their offspring to determine individual HALI susceptibility.