The natural history of chlamydia is variable and may include persisting asymptomatic infection, complications, or spontaneous resolution before treatment. Reinfection is common. We evaluated whether spontaneous resolution was associated with decreased reinfection in women returning for treatment of a positive chlamydia screening test. At enrollment, participants were tested for chlamydia, treated with azithromycin, and scheduled for a 6-month follow-up visit for repeat testing. Two hundred participants returned 1 to 12 months after treatment. Spontaneous resolution at enrollment was demonstrated in 44 (22.0%). Reinfection at follow-up occurred in 33 (16.5%), being more frequent in those with persisting infection at enrollment versus spontaneous resolution (31 of 156 [19.9%] vs 2 of 44 [4.5%]; P =. 016). Adjusting for age, the odds of reinfection was 4 times higher for participants with persisting infection at enrollment (odds ratio 4.0, 95% confidence interval, 1.1-25.6; P =. 034). Chlamydia treatment may attenuate protective immunity in some patients. © 2013 The Author. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved.