Background. A stepped-wedge, cluster randomized controlled trial assessed the effectiveness of practice facilitation (PF) for adoption of guidelines for prevention and treatment of cardiovascular disease risk factors. This study estimated the associated cost of PF for guideline adoption in small, private primary care practices. Methods. The cost analysis included categories for start-up costs, intervention costs, and practice staff costs for the implemented PF-guided intervention. We estimated the total one-year costs to operate the program, and calculated the mean and range of the cost-per-practice by quarter of the intervention. We estimated the lower and upper bounds for all salary expenses, rounding to the nearest $100. Results. Total one-year intervention costs for all 261 practices ranged from $7,900,000-$10,200,000, with program and practice salaries comprising $6,600,000-$8,400,000 of the total. Start-up costs were a small proportion (3%) of total one-year costs. Excluding start-up costs, quarter 1 cost-per-practice was the most expensive at $20,400-$26,700, and quarter 4 was least expensive at about $10,000. Practice staff time (compared with program staff time) was the majority of the staffing costs at 75-84%. Conclusions. The PF strategy cost approximately $10,000 per practice per quarter for program and practice costs, once implemented and running at highest efficiency. Whether this program is “worth it” to the decision-maker depends on the relative costs and effectiveness of their other options for improving cardiovascular risk reduction.Trial Registration. This study is retrospectively registered on January 5, 2016 at www.clinicaltrials.gov as NCT02646488. https://clinicaltrials.gov/ct2/show/NCT02646488