High-cost, medically complex patients have been a challenging population to manage in the US health care system, in terms of both improving health outcomes and containing costs. This paper evaluated the economic impact of Care One, an intensive care management program (data analysis, evaluation, empanelment, specialist disease management, nurse case management, and social support) designed to target the most expensive 1% of patients in a university health care system. Data were collected for a cohort of high-cost, medically complex patients (N = 753) who received care management and a control group (N = 794) of similarly complex health system users who did not receive access to the program. A pre-post empirical model estimated the Care One program to be associated with a per-patient reduction in billed charges of $92,227 (95% confidence interval [CI]: $83,988 to $100,466). A difference-in-difference model, which utilized the control group, estimated a per-patient reduction in billing charges of $44,504 (95% CI: $29,195 to $59,813). Results suggest that care management for high-cost, medically complex patients in primary care can reduce costs compared to a control group. In addition, significant reversion to the mean is found, providing support for the use of a difference-in-difference estimator when evaluating health programs for high-cost, medically complex patients.