BACKGROUND: Paramagnetic rim lesions (PRLs), marked by chronic inflammation and iron-loaded microglia, are linked to severe disease progression in multiple sclerosis (MS). The impact of cladribine, an immune reconstitution therapy, on PRLs remains underexplored. OBJECTIVE: To evaluate the effect of cladribine tablets on PRLs in relapsing-remitting MS (RRMS) patients and explore the association between PRLs dynamics and brain atrophy. METHODS: We conducted a retrospective analysis of 52 RRMS patients treated with cladribine in Buenos Aires between 2018 and 2021. Brain MRIs were analyzed at baseline, 12, and 24 months post-treatment, focusing on PRLs count and brain volume measurements. Statistical analyses included Wilcoxon tests, Poisson mixed models, and linear mixed models. RESULTS: The cohort included 52 patients (32 women) with a median age of 36 years (range 21-66 years). PRLs were present in 61.5% of patients at baseline. Cladribine treatment significantly reduced PRLs count (IRR=0.68, 95% CI [0.49, 0.95], p=0.02), independent of prior treatment or disease activity. While no significant relationship was found between PRLs changes and overall brain atrophy, a significant interaction between PRLs dynamics and atrophy in the right thalamus was observed (p<
0.05). CONCLUSION: Cladribine tablets are associated with a reduction in PRLs in RRMS patients, potentially influencing regional brain atrophy over time.