Background: Evobrutinib is a highly selective Bruton’s tyrosine kinase inhibitor with dual mode of action, targeting B cells and myeloid cells. Evobrutinib’s clinical efficacy in relapsing multiple sclerosis was shown in a Phase II, randomized, controlled trial NCT02975349: T1 Gd-enhancing lesions significantly decreased versus placebo at Week 24 (primary endpoint); efficacy continued through Week 48. Objectives: To report long-term efficacy of evobrutinib in patients with relapsing multiple sclerosis over combined randomized and open-label extension (OLE) study periods. Methods: During the double-blind period (DBP), patients received evobrutinib 25 mg QD, 75 mg QD, 75 mg BID, or placebo for 24 weeks, continuing treatment until 48 weeks, except the placebo group, who switched to 25 mg QD. At Week 48, patients could enter the OLE. Treatment was evobrutinib 75 mg QD (median: 48 weeks), then 75 mg BID. Efficacy was assessed by annualized relapse rate (ARR), and cumulative probability of and time to first qualified relapse (QR) in patients completing 60 weeks of OLE treatment or discontinuing. Results: Of 213 patients randomized in the DBP, 164 (77%) entered the OLE; of these, 148 (90%) completed 108 weeks in total. Compared with those initiated in other DBP arms, patients initiated on evobrutinib 75 mg BID had lower ARR (95% Cl) 0.11 (0.04, 0.25) at Week 48 and 0.12 (0.06, 0.22) at Week 108; lower cumulative probability of first QR,0.08 (0.00, 0.16) at Week 48 and 0.20 (0.08, 0.31) at Week 96. The estimated time by which 20% of patients had a QR was almost three times longer for those initiated on 75 mg BID versus placebo. Conclusions: Improvement in ARR with evobrutinib 75 mg BID at Week 48 was maintained at Week 108. Probability of and time to first QR highlighted that patients initiated on 75 mg BID achieved greater treatment efficacy than those initiated on evobrutinib 25 mg QD, 75 mg QD, or placebo.