Background: Comorbidities are common in patients with multiple sclerosis (MS), thus increasing the complexity of disease management and economic burden and worsening their prognosis and quality of life. Real-world evidence comparing comorbidities and multimorbidity patterns of commercially insured vs Medicare enrollees with MS is lacking. Objective: To evaluate the patterns of comorbidity and multimorbidity among patients with MS in a US commercially insured and Medicare Advantage population. Methods: This retrospective observational cohort study was conducted using Aetna health claims data from January 1, 2015, to October 31, 2019. Eligibility criteria were (1) at least 3 MS-related inpatient/outpatient (ICD-10-CM: G35), or disease-modifying therapy claims within 1 year (date of first claim = index date); (2) Aetna commercial health plan or Medicare Advantage medical and pharmacy benefits at least 12 months pre-/post-index; and (3) age 18 and older. Commercially insured patients, Medicare Advantage patients younger than 65 years of age, and Medicare Advantage patients 65 years and older were compared. Results: Among 5000 patients (mean [SD] age, 52.6 [12.9]; 75.2% female), 53% had commercial insurance and 47% had Medicare Advantage (59.2% disabled age <65). Medicare Advantage patients were older (age <65: 53.3 [7.9]; age ≥65: 70.8 [5.2]) vs commercial (age, 45.7 [10.2]), had greater comorbidity burden (Charlson Comorbidity Index; age <65: 1.17 [1.64], age ≥65: 1.65 [1.95]) vs commercial (0.53 [1.02]) (all P < .0001). Symptoms specific to MS (ie, malaise, fatigue, depression, spasms, fibromyalgia, convulsions) were more common among patients younger than 65 (all P < .0001). Age-related and other comorbidities (ie, hypertension, hyperlipidemia, dyspepsia, osteoarthritis, osteoporosis, glaucoma, diabetes, cerebrovascular, cancer) were more common among patients 65 years and older Medicare Advantage (all P < .0001). Multiple comorbidities were highly prevalent (median, 4 comorbidities), particularly among Medicare Advantage patients younger than 65 (median, 6) and Medicare Advantage patients 65 and older (median, 7). Conclusions: Comorbidities and multimorbidity patterns differed between patients with MS with commercial insurance and patients with Medicare Advantage. Multimorbidity was highly prevalent among patients with MS and should be considered in the context of clinical decision making to ensure comprehensive MS management and improve outcomes.