PURPOSE: This study aimed to evaluate 1) whether having a vascular comorbidity (i.e., hypertension, hyperlipidemia, heart disease, and diabetes) was associated with self-reported issues with functional activities among persons with multiple sclerosis (MS) and 2) if certain contributing factors (i.e., disability, depression, and fatigue) might explain the observed relationships. MATERIALS AND METHODS: Participants (n = 263) completed the Functional Status Index (FSI), which assessed five domains: gross mobility, hand activities, personal care, home chores, and social/role activities. After bivariate analyses, individual linear regressions were conducted for each FSI domain, controlling for demographics. Follow-up mediation analyses were done for each of the three mediators. RESULTS: Participants with vascular comorbidities endorsed more issues on all five domains, with the demographic-adjusted associations with gross mobility (b = 0.34, p = 0.002), hand activities (b = 0.15, p = 0.006), home chores (b = 0.44, p = 0.003), and social/role activities (b = 0.32, p = 0.024) remaining significant. Disability fully mediated the effects of vascular comorbidities on these domains, with partial and full mediations observed with depression and fatigue. Diabetes emerged as a significant individual comorbidity in several models. CONCLUSIONS: Vascular comorbidities, diabetes in particular, are associated with persons with MS endorsing worse ratings on functional outcomes, with disability, depression, and fatigue explaining these associations.