The purpose of this pilot study was to assess the cost-effectiveness of four different doses (based on patients’ level of cognition and activation) of a home-based care transitions intervention compared with usual care at 2 and 6 months after hospital discharge to home for 126 adult patients with three or more chronic diseases. Health care utilization was measured, and a cost-effectiveness analysis was used to estimate incremental costs and quality-adjusted life-years associated with each intervention arm. At 6 months, results from this pilot study are very promising and support cost-effectiveness for Group 2-low cognition/high activation, Group 3-normal cognition/low activation, and Group 4-normal cognition/high activation patients. However, Group 1-low cognition/low activation needs a more intensive treatment than what was provided in the intervention, because of their low cognition and activation levels. Our intervention strategies provided to the groups would be scalable to a larger patient population and across different facilities.