Background: In a 48-week Phase II study NCT02975349, in patients with relapsing multiple sclerosis, evobrutinib was generally well-tolerated. Objectives: We report long-term safety data from an ongoing open-label extension (OLE) in patients treated 60 OLE weeks or discontinuing early. Methods: During the double-blind period (DBP), 213 patients were randomized to evobrutinib 25mg QD, 75mg QD, 75mg BID or placebo for 24 weeks, continuing until 48 weeks, except placebo patients, who switched to evobrutinib 25mg QD. At Week 48, patients could enter the OLE. Treatment was evobrutinib 75mg QD (median ==48 weeks) before switching to 75mg BID. Treatment-emergent adverse events (TEAEs) were assessed throughout the OLE, immune cells at OLE Week 48, and lg levels at OLE Weeks 24 and 48. Results: TEAEs occurred in 107 (65.2%) of OLE patients (47.6% mild, 36.0% moderate, 7.9% serious), balanced across previous DBP groups; no deaths occurred. Transient aminotransferase elevations in the DBP were not observed in OLE patients continuing evobrutinib. CD19+ B cell counts decreased versus DBP baseline in all DBP evobrutinib groups, although mean values stayed in normal range, with no changes in memory B cell, T cell or NK cell counts, and no relevant change in lgG levels versus DBP baseline. Mean lgA and lgM levels increased and decreased, respectively, versus DBP baseline, but were within normal ranges. Immune cell and immunoglobulin changes following long-term treatment with evobrutinib in the OLE were consistent with those reported for the DBP. Evobrutinib did not appear associated with enhanced infection risk during the DBP or OLE. Conclusions: Safety of evobrutinib over 60 weeks of the OLE was similar to that in the DBP. Treatment was generally well-tolerated; no new safety signals were observed. OLE 48-week immune cell and lg levels were consistent with the DBP. Evobrutinib 75mg BID was not associated with increased infection risk.