Baseline data from a population-based study examining the health-related quality of life (HRQL) of MS patients about to begin disease modifying therapy was used to determine the factors associated with the HRQL of Saskatchewan adults with relapsing-remitting MS. Participants completed a self-report questionnaire regarding demographic and socioeconomic status, fatigue, comorbid medical conditions, disability level (EDSS), number of attacks in past 6 months, illness intrusiveness (Illness Intrusiveness Ratings Scale), depression (Beck Depression Inventory), and HRQL (SF-36 Health Status Survey). Multiple linear regression models were used to identify the factors associated with the physical and mental health summary scores of the SF-36. We found poorer physical HRQL in those who are female; older; not working; have musculoskeletal or respiratory problems; greater fatigue, higher disability scores, and more MS attacks. High illness intrusiveness; digestive system problems; genitourinary problems; and headaches were associated with poorer mental HRQL. Interestingly, we found an interaction between sex and age in mental HRQL, with worse mental health in older men but better mental health in older women. These findings may assist health care providers in identifying patients who may be at risk for decline in their HRQL, permitting appropriate and timely interventions.