Abstract Aims We aim to provide real-world evidence on the use of ocrelizumab for treating multiple sclerosis (MS), with specific regard to prescription pattern, adherence, persistence, healthcare resource utilization and related costs, also in relation to other disease-modifying treatments (DMTs). Methods We included 2495 people with MS from the Campania Region (South Italy) who received first or switch DMT prescription from Jan 2018 to Dec 2020, and with at least 6-month follow-up. We collected hospital discharge records, drug prescriptions, and related costs, and calculated persistence (time from first prescription to discontinuation or switch to other DMT), adherence (proportion of days covered (PDC)), annualized hospitalization rate (AHR) for MS-related hospital admissions, and DMT costs. Results Ocrelizumab was the most commonly prescribed DMT (n = 399; age = 45.74 ± 10.98 years; females = 224), after dimethyl fumarate (n = 588) and fingolimod (n = 401); 26% patients treated with ocrelizumab were naïve. When compared with ocrelizumab, the risk of discontinuation was higher for other highly active DMTs (HR = 3.78; p = 0.01), and low/medium efficacy DMTs (HR = 7.59; p < 0.01). When compared with ocrelizumab, PDC was similar to other highly active DMTs (Coeff = 0.01; p = 0.31), but higher for low/medium efficacy DMTs (Coeff = 0.09; p < 0.01). When compared with ocrelizumab, AHR was similar to other highly active DMTs (Coeff = 0.01; p = 0.51), and low/medium efficacy DMTs (Coeff = 0.01; p = 0.55). When compared with ocrelizumab, DMT monthly costs were higher for other highly active DMTs (Coeff = 92.30; p < 0.01), but lower for low/medium efficacy DMTs (Coeff = − 1043.61; p < 0.01). Discussion Ocrelizumab was among the most frequently prescribed DMTs, with 26% prescriptions to treatment-naïve patients, suggesting its relevance in addressing unmet clinical needs (e.g., first approved treatment for primary progressive MS). Ocrelizumab was associated with the highest persistence, confirming its favorable benefit-risk profile. Costs for ocrelizumab were lower than those associated to similarly effective DMTs, in absence of changes in healthcare resource utilization.