This article evaluates the long-term impacts of the Chicago Child-Parent Centers (CPC), a comprehensive early childhood program launched in the 1960s, on physical and mental health outcomes. This study follows a cohort of 1539 participants born in 1979–1980 and surveyed most recently at age 35–37 by employing a matched study design that included all 989 children who entered CPCs at ages 3 and 4 (1983-1985) and 550 comparison children of the same age from randomly selected schools participating in the usual district early childhood programs in kindergarten. Using propensity score weighting that addresses potential issues with differential attrition and non-random treatment assignment, results reveal that CPC preschool participation is associated with significantly lower rates of adverse health outcomes such as smoking and diabetes. Further, evaluating the economic impacts of the preschool component of the program, the study finds a benefit-cost ratio in the range of 1.35–3.66 (net benefit: $3896) indicating that the health benefits of the program by themselves offset the costs of the program even without considering additional benefits arising from increased educational attainment and reduced involvement in crime reported in earlier cost-benefit analyses. The findings are robust to corrections for multiple hypothesis testing, sensitivity analysis using a range of discount rates, and Monte Carlo analysis to account for uncertainty in outcomes.