Pseudomonas aeruginosa is a leading cause of infectious keratitis. Many ocular isolates of this bacterium invade corneal epithelial cells in vitro and in vivo. Antibiotic survival assays have shown that a complete core lipopolysaccharide is required for full epithelial invasion by P. aeruginosa. In this study, we show that P. aeruginosa mutants with defects in their lipopolysaccharide core and O antigen exhibited reduced viability after internalization by corneal epithelial cells. Restoration of lipopolysaccharide core and O antigen expression by complementation with the plasmid pLPS1 restored intracellular survival. P. aeruginosa strains with a complete lipopolysaccharide survived and replicated within the cells. The data suggest that lipopolysaccharide is involved in the intracellular survival and/or replication of P. aeruginosa, indicating an additional mechanism by which this important virulence factor may contribute to the pathogenesis of corneal infection.