Background: Cladribine tablets 3.5 mg/kg cumulative over 2 years (CT3.5) had significant clinical/imaging effects in patients with clinically isolated syndrome (CIS; ORACLE-MS) or relapsing-remitting MS (RRMS; CLARITY and CLARITY Extension). This analysis compared the effect of cladribine tablets on the dynamics of immune cell reduction and reconstitution in ORACLE-MS, CLARITY, and CLARITY Extension during the first year of treatment (i.e. the first course of CT1.75) in patients randomized to CT3.5. Methods: Lymphocyte subtypes were analyzed using multiparameter flow cytometry. Changes in cell counts and relative proportions of lymphocytes were evaluated at weeks 5, 13, 24, and 48. Results: Across studies, consistent and comparable selective kinetics of immune cell populations occurred following the first treatment year with CT. A rapid reduction in CD16⁺/CD56⁺ cells (week 5 nadir), a more marked reduction in CD19⁺ B cells (week 13 nadir), and a less-pronounced effect on CD4⁺ (week 13 nadir) and CD8⁺ T cells (week 24 nadir) was shown. There was little effect on neutrophils or monocytes. Lymphocyte recovery began after treatment with CT3.5. Regarding relative proportions of naïve and memory T-cell subtypes in ORACLE-MS, the proportion of naïve-like naturally occurring T-regulatory cells (nTregs) decreased, and the proportion of memory-like nTregs increased, relative to total CD4⁺ T cells. Conclusions: CT3.5 has comparable effects on the immune systems of patients with CIS or RRMS. The pronounced reduction and recovery dynamics of CD19⁺ B cells and relative changes in the proportion of some immune cell subtypes may underlie the clinical effects of CT3.5.