Background: The action of cladribine tablets (CladT) on immune cells may be key for both onset and durability of its effect in people with multiple sclerosis (MS). Objectives: To report on peripheral immune cell subset dynamics and immunoglobulin levels in the first 12 months of CladT therapy. Methods: Longitudinal evaluation of peripheral blood immune cells in patients receiving CladT in a sub-study of MAGNIFY-MS (NCT03364036). Absolute cell counts and percent change from baseline were assessed for adaptive immune cell subtypes and immunoglobulins. Immunophenotyping was completed at baseline and months 1, 2, 3, 6, and 12. Results: Full analysis set: 57 patients (median age 37 years; 61% female; ?2 relapses in previous year, 70%). Effector and regulatory B cells were reduced from Month 1 and showed a subtype-specific repopulation pattern. Change from baseline for CD19+ B cells: Month 1, -77%; Month 2, -90%; Month 12, -35%. Memory B cells: Month 1, -74%; Month 3, -93%; Month 12,-87%. Plasmablasts: Month 1, -28%; Month 3, -78%; Month 12, -51%. Regulatory B cells (CD19+, CD24bright, and CD38bright): Month 1, -45%; Month 3, +176%; Month 6, +171%; Month 12, +50%. Naïve/transitional B cells: Month 1, -79%/-61%; Month 3, -69%/+35%; Month 12, +35%/+23%. Decrease in T cell subsets was moderate and slower, nadir occurring between 3 and 6 months. T-helper 17 CD4+ and terminally differentiated effector memory CD8+ T cell counts reached nadir at Month 3 (-35% and -25%, respectively). No clinically meaningful change in serum IgG or IgM was observed over 12 months. Conclusions: Assessment of lymphocyte dynamics following CladT over 1 year demonstrates that effects occur from Month 1, and are sustained in several immune cell subpopulations. CladT exerts a pronounced effect on memory B cells, while immunoglobulin levels are unaffected over 12 months. Results suggest early onset of CladT action, underpinned by MAGNIFY-MS MRI results, may be mediated through this specific pattern of sustained decrease and reconstitution of B and T cell subtypes in a highly active MS population.