Background: Immune reconstitution therapies (IRT) for patients with multiple sclerosis are used for short, intermittent treatment periods to induce immune resetting and allow subsequent treatment-free periods. Cladribine tablets are postulated to be an IRT that causes selective and transient reductions in CD19 ⁺ B cells and T cells, followed by reconstitution of adaptive immune function. Objective: To characterize long-term lymphocyte count changes in pooled data from the 2-year CLARITY and subsequent 2-year CLARITY Extension studies, and the PREMIERE registry (Long-term CLARITY cohort). Methods: Data from patients randomized to placebo (n = 435) or cladribine tablets 10 mg (MAVENCLAD ^® ; 3.5 mg/kg cumulative dose over 2 years, referred to as cladribine tablets 3.5 mg/kg; n = 685) in CLARITY or CLARITY Extension, including time spent in the PREMIERE registry were pooled to provide long-term follow-up data. The study investigated absolute lymphocyte counts (ALC) up to 312 weeks and B and T cell subsets up to 240 weeks after the first dose, in patients receiving placebo or cladribine tablets 3.5 mg/kg administered as two short (4 or 5 days) weekly treatments at the start of months 1 and 2 in each treatment year, followed by no further active treatment. Results: Treatment with cladribine tablets 3.5 mg/kg resulted in selective reductions in B and T lymphocytes. Lymphocyte recovery began soon after treatment in each of years 1 and 2. Median ALC recovered to the normal range and CD19 ⁺ B cells recovered to threshold values by week 84, approximately 30 weeks after the last dose of cladribine tablets in year 2. Median CD4 ⁺ T cell counts recovered to threshold values by week 96 (approximately 43 weeks after the last dose of cladribine tablets in year 2). Median CD8 ⁺ cell counts never dropped below the threshold value. Conclusion: These results show the dynamics of lymphocyte count changes following treatment with cladribine tablets 3.5 mg/kg. The immune cell repopulation results provide further evidence that cladribine tablets may represent a form of IRT.