Background: In natalizumab treated patients several hematopoietic abnormalities including erythroblasts, myeloblasts and neutrophilic precursors in peripheral blood have been described. So far, long term effects of the hematopoietic changes have not been reported. Objective: To describe hematopoietic abnormalities in longitudinally monitored MS patients treated with natalizumab. Patients treated with dimethyl fumarate, teriflunomide and fingolimod served as controls. Secondly, the relation between natalizumab serum levels and the occurrence of hematopoietic abnormalities was explored. Methods: 212 natalizumab treated patients were included, 91 patients with available baseline samples (998 follow-up samples) were compared with patients with dimethyl fumarate (n = 166, 1154 samples), teriflunomide (n = 38, 228 samples) and fingolimod (n = 114, 853 samples). One hundred twenty one patients without baseline samples (1952 follow-up samples) were included in the follow-up group. Results: More than half of all natalizumab treated patients developed hematopoietic abnormalities, almost a quarter had erythroblasts. Natalizumab use was associated with an increased risk of developing abnormalities in comparison to oral treatment, with a corrected hazard ratio of 2.3, 10.0 and 8.1 in comparison to fingolimod, dimethyl fumarate and teriflunomide respectively. No difference in developing abnormalities was observed in relation to natalizumab serum concentrations. None of the patients developed a hematologic malignancy during follow up. Conclusion: Hematopoietic abnormalities are common during natalizumab treatment. Given the lack of consequences of this finding during long-term follow-up, it is generally justifiable to refrain from further diagnostic procedures when observing hematopoietic abnormalities in patients using natalizumab.