This study evaluated the effectiveness (changes in health behaviors, health status, and health service utilization) of a self-management program for chronic disease designed for use with a heterogeneous group of chronic disease patients. It also explored the differential effectiveness of the intervention for subjects with specific diseases and comorbidities. The study was a six-month randomized, controlled trial at community-based sites comparing treatment subjects with wait-list control subjects. Participants were 952 patients 40 years of age or older with a physician-confirmed diagnosis of heart disease, lung disease, stroke, or arthritis. Health behaviors, health status, and health service utilization, as determined by mailed, self-administered questionnaires, were measured. Treatment subjects, when compared with control subjects, demonstrated improvements at 6 months in weekly minutes of exercise, frequency of cognitive symptom management, communication with physicians, self-reported health, health distress, fatigue, disability, and social/role activities limitations. They also had fewer hospitalizations and days in the hospital. No differences were found in pain/physical discomfort, shortness of breath, or psychological well-being. An intervention designed specifically to meet the needs of a heterogeneous group of chronic disease patients, including those with comorbid conditions, was feasible and beneficial beyond usual care in terms of improved health behaviors and health status. It also resulted in fewer hospitalizations and days of hospitalization.