Background: Ofatumumab is an anti-CD20 monoclonal antibody approved for subcutaneous administration for the treatment of relapsing multiple sclerosis (MS), but intravenously administered ofatumumab has been investigated in a phase 2 trial and used off-label. The objective of the present study was to assess disease activity and side effects in relation to longer-term intravenous ofatumumab treatment of MS and related disorders. Methods: We conducted a retrospective study of patients treated off-label with intravenous ofatumumab for MS, neuromyelitis optica spectrum disease (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) at the Danish Multiple Sclerosis Center. Data was retrieved from the Danish Multiple Sclerosis Registry and through medical chart review. Results: Fifty patients were identified with a median treatment duration of 2.2 years. Annualized relapse rate decreased from 1.03 at baseline to 0.38 during ofatumumab treatment. At 24 months, the probability of having experienced a relapse was 55% and confirmed disability worsening 7%. Frequency of infusion-related reactions was 86% during the first infusion and 42% during the last infusion. Six experienced infections requiring hospitalization. Conclusion: Our data indicate a reduction of relapse frequency, stabilization of disability worsening and an acceptable safety profile, although we observed a higher frequency of infusion reactions compared to data from other intravenously administered anti-CD20 monoclonal antibodies. The study supports a class effect of anti-CD20 monoclonal antibodies and the hypothesis that complement activation may be associated to a higher frequency of infusion related reactions.