The rate of clearance of Neisseria gonorrhoeae in vaginal specimens harvested from inbred Balb/c and outbred (Institute of Cancer Research [ICR]) white mice, previously primed with saline or beta-estradiol and then challenged with live gonococci, was determined. Survival of gonococci was significantly (P < 0.05) better in estradiol-primed mice from both inbred and outbred lines at 24 h after challenge. Vaginal clearance of gonococci from ICR mice parenterally primed with a gonococcal PI-B synthetic peptide and then orally immunized with gamma irradiated, protein-III deficient gonococcal cells was significantly (P < 0.001) faster than in corresponding nonimmunized, estradiol-primed controls. The more rapid vaginal clearance in the orally immunized mice was correlated with an elevated subcutaneous chamber ID50% (> 100,000 colony forming units) determined for the same groups of mice. Peptide-primed mice orally immunized with irradiated Escherichia coli cells demonstrated a chamber ID50% of < 100 CFU and were significantly (P < 0.01) slower to clear gonococci following vaginal challenge. High levels of specific IgA and IgG antibodies to gonococci were detected by an enzyme-linked immunosorbent assay in vaginal wash specimens from orally immunized mice. However, high antibody titers were not always predictive of an increased resistance to vaginal challenge. These models may be helpful in providing more economical and accessible in vivo methods for screening certain gonococcal vaccine candidates before more expensive testing in chimpanzees or humans.