Background: Clinical guidelines have traditionally advised annual Chlamydia trachomatis screening for women younger than 25 years of age. Objective: To assess the cost-effectiveness of recently proposed strategies for chlamydia screening. Design: State transition simulation model; cost-effectiveness analysis. Data Sources: Published literature. Target Population: Sexually active U.S. women 15 to 29 years of age. Time Horizon: Lifetime. Perspective: Modified societal. Interventions: Four strategies targeted to 3 specific age groups (15 to 19 years, 15 to 24 years, and 15 to 29 years): 1) no screening, 2) annual screening for all women, 3) annual screening followed by 1 repeated test within 3 to 6 months after a positive test result, and 4) annual screening followed by selective semi-annual screening for women with a history of infection. Outcome Measures: Clinical events (for example, pelvic inflammatory disease, chronic pelvic pain, ectopic pregnancy, and infertility), lifetime costs, quality-adjusted life expectancy, and incremental cost-effectiveness ratios. Results of Base-Case Analysis: Annual screening in women 15 to 29 years of age followed by semiannual screening for those with a history of infection was the most effective and cost-effective strategy. It consistently had an incremental cost-effectiveness ratio less than $25 000 per quality-adjusted life-year (QALY) compared with the next most effective strategy. When the indirect transmission effects of a 10-year screening program on the probability of infection in uninfected women (that is, per-susceptible rate of infection) were considered, all strategies became more cost-effective. Results of Sensitivity Analysis: Results were sensitive to the annual incidence of chlamydia, probability of persistent infection, screening test costs, and costs of treating long-term complications. Each variable was associated with threshold values beyond which screening became cost-saving. In probabilistic analysis, annual screening in women 15 to 29 years of age followed by semiannual screening for those with a history of infection had an incremental cost-effectiveness ratio less than $50 000 per QALY in 99% of simulations. Limitations: Uncertainty about the natural history of chlamydial infection and consideration of only the indirect transmission effects of C trachomatis screening. Conclusions: Annual C. trachomatis screening for all women 15 to 29 years of age and selective targeting of those with a history of infection for semiannual screening is very cost-effective compared with other well-accepted clinical interventions.