Background: : The clinical manifestation of multiple sclerosis (MS) is highly variable. Factors influencing phenotypic heterogeneity are not well known since most studies have relied on the Expanded Disability Status Scale which has modest inter/intra-rater reliability. We therefore sought to investigate other reliable and valid measures of impairment. Methods: : We constructed a retrospective cohort of 2083 relapsing remitting MS patients using electronic health records to identify prognostic factors of Timed 25-Foot Walk (lower limb disability), Performance Scales Sum (perceived global disability), and Patient Health Questionnaire 9 (a depression tool). Patients had a clinical visit between 1/1/2008 and 5/29/2012, and at least one additional visit within approximately 3 years; the cohort consisted of 16,538 visits. The outcomes and predictors were extracted from the records. Longitudinal models were conducted, and sex- and race-specific differences were explored. Results: : Walking speeds were slower in females, black patients, ever smokers, and Medicaid/Medicare beneficiaries. Higher body mass index (BMI), older age, longer disease duration, lower median income, and higher depression scores also predicted slower walking speeds. Older age, higher BMI, lower median income, higher depression scores, ever smokers and Medicaid/Medicare beneficiaries were associated with higher global disability. Those who were of younger age, higher BMI, lower median income, ever smoked, and on Medicaid had higher depressive scores. The effect of age and BMI on depressive scores were restricted to female and white patients, respectively. Conclusion: : We identified multiple longitudinal predictors of disability in relapsing remitting patients. Modifiable factors (including smoking and BMI) and adverse socioeconomic conditions were independently, and negatively associated with walking speed, global disability, and depression.