Chlamydia trachomatis is a major cause of sexually transmitted disease (STD) worldwide. Antibiotics are effective in treating infection; however, reinfection is common. This observation has led to the conclusion that infection fails to elicit a protective antichlamydial immune response. It was postulated that high reinfection rates might be due to early eradication of organisms from genital tissue after antibiotic intervention, which could negatively influence the development of naturally acquired protective immunity. This hypothesis was tested by use of a murine model of female genital infection. The findings show that doxycycline intervention of infection, although very effective in eradicating chlamydiae from genital tissue and preventing upper genital tract disease, significantly inhibits the development of protective immunity. If antibiotic intervention of human chlamydial genital infection has a similar effect on protective immunity, it could have important implications in the understanding of immunity to infection and future public health efforts to control chlamydial STD.