OBJECTIVES: Natalizumab (NTZ) and ocrelizumab (OCR) are well-established therapies and commonly considered first-line for newly diagnosed people with multiple sclerosis (pwMS) in the United States. However, there is a paucity of data comparing healthcare resource utilization (HCRU) and relapse outcomes between NTZ and OCR in this population. METHODS: This retrospective longitudinal analysis using the Komodo Health Claims Database included newly diagnosed treatment-naïve pwMS aged 18-64 years with ≥1 prescription claims for NTZ or OCR between 1 January 2017 and 31 March 2022. Propensity score matching (1:2) was used to balance baseline characteristics. Outcomes included HCRU and costs, as well as relapses. Relapse events were identified using a claims‑based algorithm. RESULTS: The analysis included 1,261 NTZ- and 2,522 OCR-treated pwMS. First-line NTZ treatment was associated with significantly lower annualized rates of all-cause inpatient admissions (rate ratio = 0.61, 95% CI = 0.44-0.85; p = 0.003) and costs as well as emergency department visits (rate ratio = 0.80, 95% CI = 0.68-0.96; p = 0.015) than first-line OCR treatment. Annualized relapse rates (ARR) were significantly lower with first-line NTZ versus OCR treatment (0.20 vs. 0.28; rate ratio = 0.70, 95% CI = 0.59-0.82; p < 0.001). There was also a significantly higher probability of pwMS being relapse-free at 3 years with first-line NTZ versus OCR (69.9% vs. 63.9%; p = 0.002). LIMITATIONS: This study has limitations inherent to claims data, including limited clinical detail and reliance on a claims-based relapse algorithm. CONCLUSIONS: This real-world, claims-based analysis demonstrates that first-line NTZ treatment was associated with significantly lower inpatient and emergency department HCRU, inpatient healthcare costs, and ARR than first-line OCR treatment. Given the paucity of comparative data among these therapies in newly diagnosed MS patients, these results provide valuable real-world evidence to help guide treatment decisions in this group.