The interaction of bacteria belonging to several genera with the bladder epithelium was studied. An in vivo rat bladder model system was used to evaluate the cytopathic effects of members of eight representative genera of bacteria and six strains ofEscherichia coli on the bladder surface. Alterations were noted mainly with the Gram-negative bacteria (Escherichia, Klebsiella, Enterobacter, Proteus, Pseudomonas), although some strains were associated with more cytopathology than others. Foci of cytopathology consisted of swelling, exfoliated epithelial cells, strand formation, and ulceration. Aggregates of bacteria, epithelial cells, and debris were shed into the bladder lumen. In contrast, members of three genera of Gram-positive organisms (Lactobacillus, Streptococcus, Staphylococcus) caused little or no cytopathology. The study strongly suggests that the bladder responds in a relatively uniform manner to viable Gram-negative organisms, while the response to Gram-positive organisms is minimal.