BACKGROUND: Studies of the natural history of genital chlamydial infections in humans are sparse and have had study design limitations. An improved understanding of chlamydial natural history may influence recommendations for elements of control efforts such as chlamydia screening frequency or time parameters for partner notification. METHODS: Addressing limitations of prior studies in part, we are prospectively studying chlamydial natural history in sexually transmitted diseases clinic patients in the interval between screening and returning for treatment of positive chlamydial tests. Results of repeat chlamydial testing and clinical outcomes and their associated predictors are being evaluated. RESULTS: In the initial 129 subjects, 89% were female, 88% were black, median age was 21 years, and the median interval between screening and treatment was 13 days. Based on nucleic acid amplification testing at treatment, spontaneous resolution of chlamydia occurred in 18%. Resolution was somewhat more common in subjects with longer intervals between screening and treatment. Persisting infections more often progressed to develop clinical signs at the time of treatment (e.g., urethritis or cervicitis). Two women and one man developed chlamydial complications between screening and treatment. CONCLUSIONS: Our findings demonstrate that although spontaneous resolution of chlamydia is common, many persons with persisting chlamydia progress to develop signs of infection and some develop complications. © Copyright 2008 American Sexually Transmitted Diseases Association.