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Cladribine tablets are a treatment for multiple sclerosis (MS) with effects on lymphocytes’, yet its mode of action has not been fully established. Here, we evaluated the effects of cladribine on mitochondrial DNA integrity in human lymphocytes. We treated cultured human T-cell lines (CCRF-CEM and Jurkat) with varying concentrations of cladribine to mimic the slow cell depletion observed in MS. The CCRF-CEM were slower proliferating and more susceptible to cladribine than Jurkat cells. In both cells mitochondrial protein synthesis, mtDNA copy number and Mitochondrial Cytochrome-C Oxidase-I mRNA mutagenesis was not affected by cladribine, while some caspase-3 cleavage was detected in Jurkat cells at 100 nM concentration. Cladribine treatment at concentrations up to 10 nM in CCRF-CEM and 100 nM in Jurkat cells did not induce significant increase in mtDNA somatic mutations. We analyzed ex vivo peripheral blood mononuclear cells from 8 MS patients and 4 controls. Subtle effect of cladribine on cell viability was found at 5 nM, however, we did not find any differences in mtDNA somatic mutations in separated lymphocyte subpopulations (CD4+, CD8 + and CD19+) between treated vs. non-treated cells. Overall, the mutation rate in mtDNA was similar in MS-patients and controls. When different lymphocyte subpopulations were compared, greater mtDNA mutation levels were detected in CD8+ (p = 0.014) and CD4+ (p = 0.038) as compared to CD19 + cells, these differences were independent of cladribine treatment. We conclude that cladribine has no detectable mutagenic effect on the mitochondrial genome of cultured lymphocytes nor does it impair mitochondrial function in human T-cell lines.