Background: Persons with multiple sclerosis (MS) have consistently reported lower levels of self-esteem compared with the general population. Despite this, very little is known about the antecedents and consequences of self-esteem in persons with MS. Objectives: To examine (1) physical activity and social support as potentially modifiable correlates (i.e., antecedents) of self-esteem and (2) physical and psychological health-related quality of life as possible consequences of self-esteem in persons with MS. Methods: Participants (N = 46) wore an Actigraph accelerometer for 7 days and then completed a battery of questionnaires, including the Rosenberg Self-Esteem Scale (RSES), Multiple Sclerosis Impact Scale (MSIS-29), and Social Provisions Scale (SPS). The data were analyzed using PASW Statistics 18. Results: Bivariate correlation analysis indicated that average daily step counts (r = .298, p = .026) and social support (r = .366, p = .007) were significantly correlated with self-esteem. Multiple linear regression analysis indicated that only social support was a significant predictor of self-esteem scores (β = .411, p = .004); pedometer steps approached significance as a predictor of self-esteem (β = .178, p = .112). Bivariate correlation analysis further indicated significant negative associations between self-esteem and physical (r = -.391, p = .004) and psychological (r = -.540, p = .0001) domains of health-related quality of life (HRQOL), indicating that higher self-esteem was associated with more positive HRQOL. Conclusions: Social support is a potentially modifiable variable that may be important to target when designing interventions to improve self-esteem and this might have implications for improving physical and psychological HRQOL in persons with MS. © 2012 American Psychological Association.