BACKGROUND: Cladribine tablets have recently become available in the Netherlands for patients with relapsing remitting MS (RRMS). A network meta-analysis has indicated that cladribine tablets reduce the frequency and severity of relapses and delay disability progression compared to current standard of care. OBJECTIVES: To evaluate the cost-effectiveness of cladribine tablets compared to alternative options in the treatment of RRMS patients with high disease activity (HDA) and patients with rapidly evolving severe (RES) MS, in the Netherlands. METHODS: A Markov model was developed simulating costs and effects of RRMS treatment. For HDA, alemtuzumab and fingolimod were used as comparators; natalizumab was used for the RES sub-population. The analysis includes a full societal perspective, including indirect medical costs, productivity costs, costs for informal care and a value-of-information (VOI) analysis. RESULTS: For the HDA sub-population, treatment with cladribine tablets was the dominant strategy compared to alemtuzumab and fingolimod with respectively 50.9% and 98.2% probability of being cost-effective at a threshold of €50,000 per QALY gained and a net monetary benefit (NMB) of €3,860 and €150,255, respectively. For the RES sub-population, treatment with cladribine tablets dominated treatment with natalizumab with 94.1% probability of being cost-effective at a threshold of €50,000 per QALY gained and a NMB of €123,048. The probabilistic sensitivity analyses showed significant overlap in the credible intervals for total lifetime QALY outcomes and costs of cladribine and all relevant comparators. The population-level VOI amounts to €19,295,441. CONCLUSIONS: Treatment of RRMS with cladribine tablets is cost-effective versus alemtuzumab and fingolimod in HDA patients, and cost-effective versus natalizumab in RES patients compared with current standard of care in the Netherlands, at a QALY threshold of €50,000. Cladribine tablets was dominant in all base case analyses. The probabilistic sensitivity analyses outcomes indicated that outcomes for cladribine tablets versus the comparators are surrounded by uncertainty.