The need to provide women with a partner-independent method of prophylaxis against sexually transmitted disease (STD) agents, including Chlamydia trachomatis, has led to a directed effort to develop a vaginally applied, broad-spectrum antimicrobial preparation that is both safe and effective. Using a murine model of C. trachomatis lower genital tract infection, we tested the ability of various vaginally applied chemicals to alter the course of infection in female mice challenged with infectious doses ranging from 10(3) to 10(6) inclusion forming units of an oculogenital serovar of C. trachomatis. When administered in a methylcellulose/propylene glycol-based gel 15 minutes prior to challenge, four widely used topical antimicrobials (benzalkonium chloride, chlorhexidine, nonoxynol-9, and polymyxin B) were shown to protect against infection. These results support the possibility that this type of interventional method may be a clinically relevant means of prophylaxis against sexually transmitted infection with C. trachomatis, the most common bacterial STD agent.