Purpose: The aim of this study was to investigate whether persistent leisure-time physical activity, adjusted for genetic liability and childhood experiences, protects against chronic diseases, early signs of disability, and loss of life satisfaction. Methods: From 5663 healthy adult twin pairs, we identified 146 pairs who were discordant for both intensity and volume of leisure physical activity in 1975 and 1981. Of them, both members of 95 pairs were alive and participated in our follow-up study in 2005 when chronic diseases (such as diabetes, cardiovascular disease, and osteoarthritis), life satisfaction, and disability were assessed by a structured telephone interview. The mean age of the participants was 58 yr (range = 47–79 yr) in 2005. Paired tests were used in the analyses. Results: At the end of follow-up, the active cotwins had a decreased risk of reporting at least one chronic diseases, whereas active monozygotic (MZ) twins had two or more chronic diseases significantly less often than their inactive cotwins (odds ratio [OR] = 0.14, P = 0.031). Overall, the risk for type 2 diabetes or glucose intolerance (OR = 0.09, P = 0.022) and elevated blood pressure (OR = 0.46, P = 0.039) was decreased among the active cotwins. These effects were seen clearly among dizygotic twins but not always among small number of monozygotic twins. The active cotwins reported greater life satisfaction (P = 0.047) and tended to be less likely to be hospitalized (P = 0.065), although active cotwins had somewhat more sports-related injuries (OR = 1.9, P = 0.051) than inactive cotwins. Studied disability variables did not differ between the active and the inactive cotwins. Conclusions: Physical activity reduces the risk for chronic diseases and helps in maintaining life satisfaction. However, genetic factors may play a role in this association because some findings emerged more clearly among dizygotic than monozygotic twins discordant for physical activity.