OBJECTIVES: To examine the long-term relationships between costs, utilization, and patient-centered medical home (PCMH) clinical practice systems. STUDY DESIGN: Clinical practice systems were evaluated at baseline by the Physician Practice Connections-Research Survey (PPC-RS). Annual costs and utilization of a retrospectively constructed cohort of 58,391 persons receiving primary care at 1 of 22 medical groups over a 5-year period (2005-2009) were compared. METHODS: Multivariate regressions adjusting for patient demographics, health status, and autoregressive errors compared PPC-RS scores and study outcomes for the entire cohort and 3 subcohorts defined by medical complexity (medication count 0-2 [n = 29,657], 2-6 [n = 19,505], >7 [n = 9229]). Outcomes (adjusted to 2005 dollars) were total costs, outpatient costs, inpatient costs, inpatient days, and emergency department (ED) use. RESULTS: For the entire cohort, a 10% increase in PPC-RS scores was associated with 3.9 (medication count: 0-2), 6 (3-6), and 11.6 (>7) fewer ED visits per 1000 in 2005; and 5.1, 7.6, and 13.6 fewer ED visits in 2009. That 10% increase was not associated with the 0-2 medication subcohort's total (-$22/person in 2005; $184/person in 2009), outpatient (-$11/person in 2005; $42/person in 2009), or inpatient ($26/person in 2005; $29/person in 2009) costs. However, it was associated with significantly decreased total (-$446/person in 2005; -$184/person in 2009) and outpatient (-$241/person in 2005; -$54/person in 2009) costs for the most medically complex subcohort (>7 medications). CONCLUSIONS: Association of PCMH clinical practice systems with reduced costs appears limited to the most medically complex patients.