The development of effective vaginal microbicides is paramount in the fight against the spread of sexually transmitted infections. Preclinical testing of candidate microbicides for the prevention of gonorrhea has been seriously hindered by the lack of an animal model. We assessed the efficacy of 7 promising formulated agents--CarraGuard, Ushercell, [poly]sodium 4-styrene sulfonate (T-PSS), PRO 2000, ACIDFORM, cellulose acetate phthalate (CAP), and BufferGel--by use of a mouse model of Neisseria gonorrhoeae genital tract infection. Mice received test agent, relevant placebo, or no treatment, followed by intravaginal N. gonorrhoeae challenge. N. gonorrhoeae colonization was tested by vaginal culture. CarraGuard, Ushercell, and T-PSS demonstrated significant protection, compared with control agents and no treatment. PRO 2000, ACIDFORM, and CAP showed significant protection, compared with no treatment but not compared with respective control agents. Mice that received BufferGel were provided significant protection, compared with untreated control mice; no placebo was tested. The findings of the present study suggest that topical agents may effectively reduce N. gonorrhoeae infection and that further evaluation is warranted.