Natural host resistance to Pseudomonas aeruginosa corneal infection is regulated by two complementing dominant genes PsCR1 and PsCR2 (RS Berk, MA Leon, LD Hazlett. Infect Immun 26:1221-1223, 1979). In this study we have demonstrated a third dominant gene, which determines susceptibility to P. aeruginosa-induced eye damage. This gene was designated as PsCS. The F1 progeny from matings between the resistant DBA/2J strain and the susceptible strain C57BL/6J and C3H/HeJ displayed the susceptibility phenotype. Backcross and F2 studies using the C3H/HeJ and DBA/2J strains suggested the presence of two linked PsCS loci.