Multiple sclerosis (MS) is associated with a large reduction in physical activity behavior, and emerging evidence indicates that this reduction might be correlated with symptoms and self-efficacy. The present study examined the nature of the associations among MS-related symptoms, exercise self-efficacy, and physical activity behavior in 80 individuals with a definite diagnosis of MS. Participants completed a measure of MS-related symptoms and self-efficacy and then wore an accelerometer for seven days. Both the frequency of overall symptoms and the frequency of motor symptoms had significant moderate inverse relationships with physical activity behavior (r = -0.47, P < 0.0001 and r = -0.49, P < 0.0001, respectively). Additionally, exercise self-efficacy was significantly and moderately correlated with physical activity (r = 0.39, P < 0.0001) and had significant and moderate inverse relationships with overall symptom frequency (r = -0.40, P < 0.0001) and motor symptom frequency (r = -0.30, P = 0.008). Path analysis demonstrated that both overall symptoms and motor symptoms had direct effects on physical activity as well as indirect effects on physical activity by way of self-efficacy. Such results suggest that the management and monitoring of MS-related symptoms may play an important role in encouraging physical activity adoption and maintenance in individuals with MS. © 2008 U.S. Cancer Pain Relief Committee.