Background and purpose Cardiovascular risk factors and comorbidities can affect the prognosis of multiple sclerosis (MS). The Framingham risk score is an algorithm that can estimate the 10‐year risk of developing macrovascular disease. Our objectives were to evaluate the possible association between the Framingham risk score at baseline and MS relapses, disability, and disease‐modifying therapy (DMT) choices over a 5‐year follow‐up. Methods This is a retrospective cohort study including 251 MS subjects. At baseline, we calculated the Framingham risk score considering the following variables: age, sex, diabetes, smoking, systolic blood pressure, and body mass index. MS outcomes including relapses, disability, and treatments were collected over 5 years. Cox proportional regression models were employed to estimate hazard ratios (HRs). Results A one‐point increase in the Framingham risk score was associated with 31% higher risk of relapse (HR = 1.31; 95% confidence interval [CI] = 1.03, 1.68), 19% higher risk of reaching of EDSS 6.0 (HR = 1.19; 95% CI = 1.05, 3.01), and 62% higher risk of DMT escalation (HR = 1.62; 95% CI = 1.22, 3.01). Conclusions Higher cardiovascular risk was associated with higher risk of relapses, disability, and DMT escalation in MS. Early identification, correction, and treatment of cardiovascular comorbidities should be carefully considered within MS management.