BackgroundOcrelizumab is the only disease-modifying therapy (DMT) approved for the treatment of people with primary progressive multiple sclerosis (pwPPMS). ObjectivesTo provide real-world evidence of ocrelizumab effectiveness and safety in pwPPMS in Croatian MS centers. MethodsA retrospective observational multi-center study of pwPPMS who were started on ocrelizumab in 7 MS centers in Croatia. ResultsWe identified 230 pwPPMS of whom 176 fulfilled the inclusion criteria. The median follow-up of the cohort was 2.73 (0.51–5.77) years. During the follow-up, 50 (28.4%) pwPPMS experienced confirmed disability worsening (CDW) and 19 (10.8%) stopped treatment with ocrelizumab. Baseline EDSS >5 was a statistically significant positive predictor for the development of CDW and/or stop of the treatment due to any cause (OR 2.482, 95% C.I. 1.192–5.166, p = 0.015). However, there was no significant difference in the development of CDW and/or stop of the treatment due to any cause if stratifying the patients based on active PPMS, age at treatment start (≤55 years vs >55 years), disease duration at treatment start (≤10 years vs >10 years), or EDSS at treatment start (≤5.0 vs >5.0). During the follow-up, 26 (14.8%) pwPPMS experienced infusion reactions, 64 (36.4%) had an infection and 4 (2.3%) developed a tumor. The percentage of pwPPMS with low levels of IgG was persistently above 10% and with low levels of IgM was persistently above 20% after cycle 4. ConclusionOur real-world data support the use of ocrelizumab in a much broader pwPPMS population than in the original randomized controlled trial.