Objective: Quality of life (QOL) is compromised among individuals with multiple sclerosis (MS). Physical activity has been positively associated with QOL, but little is known about the factors that explain and/or confound the relationship in those with MS. On the basis of a social-cognitive perspective and previous research, the authors tested the hypothesis that physical activity would be indirectly associated with QOL through a mediated pathway that included self-efficacy and functional limitations, after controlling for perceived social support. Participants: Participants were 196 individuals with a definite diagnosis of MS living in the Midwest region of the United States who completed a battery of questionnaires and wore a pedometer and accelerometer for a 7-day period. Results: Covariance modeling analyses indicated that physical activity was indirectly associated with QOL through a pathway that included self-efficacy and functional limitations, and the pattern of relationships was independent of the perception of social support. Conclusions: The findings support physical activity as a possible modifiable behavior for mitigating reductions of QOL in those with MS and suggest that a social-cognitive model aids in the understanding of physical activity's relationships with QOL. © 2007 APA, all rights reserved.