This study was carried out to determine whether levels of physical activity of patients with various chronic diseases are associated with subsequent functioning and well-being. It was an observational 2-year longitudinal design. The setting was offices of medical and mental health practices within health maintenance organizations, large multispecialty groups, and solo practices or small single-specialty group practices in three U.S. cities. Included in the study were 1758 adult patients with one or more of the following: diabetes, hypertension, congestive heart failure, recent myocardial infarction, depressive symptoms, or current depressive disorder. Outcome measures included physical, role, and functioning; energy/fatigue; pain intensity; sleep problems; depressed affect, anxiety, positive affect, and overall psychological distress/well-being; health distress; and current health perceptions. Cross-sectional (base-line), 2-year endpoint, and change score relationships were evaluated between baseline levels of physical activity and each outcome, controlling for chronic conditions, comorbidity, smoking, alcohol use, overweight, self-reported adherence, and other patient and study characteristics. Higher baseline levels of exercise were uniquely associated with better functioning and well-being at baseline and 2 years later for some measures. The magnitude of the differences varied by disease group, but tended to be between 0.17 and 0.39 of the baseline SD. Greater levels of exercise are associated with feeling and functioning better for patients with chronic conditions over a 2-year period, suggesting that this is a fruitful area for further study using controlled interventions.