The authors examined the role of the complement system in host defense against Pseudomonas aeruginosa endophthalmitis. Guinea pigs received intravitreal injections of P. aeruginosa, and comparisons were made between bacterial counts from the vitreous of control guinea pigs and experimental guinea pigs that underwent systemic decomplementation with cobra venom factor. In group 1 (intravitreal injection of 42 organisms), bacterial counts were significantly higher in the vitreous of decomplemented guinea pigs versus control guinea pigs at days 1, 2, and 3 after intravitreal injection but not at day 7 when complement levels returned to normal. In group 2 (intravitreal injection of 102 organisms), bacterial counts were significantly higher in the vitreous of experimental guinea pigs versus control guinea pigs only at day 1 with no statistically significant differences thereafter. In group 3 (intravitreal injection of 150 bacteria), there were no significant differences in bacterial counts in the vitreous of experimental versus control guinea pigs. Our results in group 1 suggest that partially decomplemented guinea pigs show impaired host defense to P. aeruginosa and that this defense is restored as complement levels return to normal. Intravitreal injection of higher numbers of P. aeruginosa as in a group 3 overwhelms and obscures any beneficial effect of the complement system on host defense.