The role of complement components C3 and C5 was examined in murine corneal infection induced by Pseudomonas aeruginosa. DBA/2 and Swiss-Webster mice are naturally resistant to experimental P. aeruginosa corneal infection. Mice of these two strains are able to restore a clear cornea within 4-6 weeks following Pseudomonas corneal challenge and are genetically deficient in the fifth component of complement. In contrast, ocular infection of congenic C5-deficient B10.D2o/Sn or normocomplementemic B10.D2n/Sn mice results in an identical pattern of susceptibility in which corneal perforation and phthisis bulbi occur. Taken together, these results indicate that C5 plays little or no role in susceptibility or resistance to Pseudomonas eye infection. In contrast, depletion of C3 in normally resistant DBA/2 mice using cobra venom factor (CoVF) diminishes the ability of these mice to restore a clear cornea following Pseudomonas infection. A single inoculation of CoVF, 24 hours prior to ocular challenge, is as effective in altering the response of DBA/2 mice as is continuous depletion of C3 during the course of infection using multiple inoculations of CoVF. Mice that are unable to clear Pseudomonas ocular infection following CoVF treatment regain this ability when the contralateral eye is infected after recovery of normal levels of C3. Depletion of C3 by CoVF treatment of DBA/2 mice, which had previously restored a clear cornea following Pseudomonas eye infection, again renders these mice susceptible.