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Background With >1.4 million cases in the United States reported to the Centers for Disease Control and Prevention in 2012, Chlamydia trachomatis infection is a major public health concern. We examined the impact of a C trachomatis vaccination program using a decision-analysis model to estimate the effects of vaccination on C trachomatis –associated costs and morbidity. Methods We developed a Markov model considering a cohort of 2158117 US females aged 9 to 26 years. Morbidity, death, and healthcare–associated costs associated with chlamydial infection of mothers and fetuses/neonates were calculated over a 17-year time frame. We developed 2 major comparison arms, namely, a C trachomatis vaccination program and no C trachomatis vaccination program. Base-case efficacy and coverage were set to those of human papillomavirus in the United States with all variables, including efficacy and coverage, ranged in sensitivity analyses. Results On the basis of a base-case analysis, a vaccination program would cost an estimated $710 million for a cohort of 2158117 women over a 17-year period, an increase of $41 million over having no vaccination program. A vaccination program would prevent 34000 cases of C trachomatis infection and 5976 cases of pelvic inflammatory disease. Conclusions A C trachomatis vaccination program results in increased cost to the healthcare system but averts significant morbidity and death. [ABSTRACT FROM AUTHOR]