The effects of oral immunization with a recombinant vaccine expressing chlamydial lipopolysaccharide (LPS) on subsequent ocular challenge with Chlamydia trachomatis were studied in cynomolgus monkeys. Groups of four or five monkeys were given an oral vaccine containing 5 X 10(8) parent or recombinant Escherichia coli on days 0, 14, and 35 and were challenged with either 2 X 10(3) or 5 X 10(3) inclusion forming units of viable purified elementary bodies on day 42. On clinical and microbiologic grounds, oral immunization failed to protect monkeys against subsequent ocular challenge. Antichlamydial IgG or IgA antibodies were not induced by oral vaccination, and the antibody response following ocular challenge was similar in vaccinated and nonvaccinated animals. Paradoxically, however, while nonvaccinated control animals developed antibodies against chlamydial LPS detectable by immunoblotting after chlamydial challenge, the LPS vaccinated animals did not. This study demonstrates that the oral recombinant vaccine expressing chlamydial LPS was ineffective in protecting against chlamydial eye infection and strongly suggests that chlamydial LPS may not be an important antigen for protective immunity against chlamydia.