OBJECTIVES: To assess the cost-effectiveness of fingolimod as a second-line therapy for patients with highly active relapsing-remitting multiple sclerosis using a Markov model applied to Greece. METHODS: The analysis was undertaken from the perspective of the Greek NHS and the model was populated with data drawn from the literature and national published sources. Two cohorts of patients, one for the intervention and one for the comparator treatment sequence, are simulated in the model over a 50 year time horizon. Each patient in a given cohort is treated with four lines of treatment or removed from treatment due to death. The analysis is based on the subgroup of highly active relapsing-remitting MS patients despite treatment with a previous DMT as this represents fingolimod’s main target population. The discount rate was 3.5% per year. Extensive sensitivity analysis was also undertaken.  RESULTS: This analysis has shown that the use of fingolimod as second-line treatment compared to DMF in these patients results in an incremental cost-effectiveness ratio of €32,939 per QALY gained over a patient’s lifetime for Interferon-beta1-aSC – Fingolimod – BSC – BSC compared to Interferon-beta1-aSC – DMF – BSC – BSC, in €33,783 for Interferon-beta1-aIM – Fingolimod – BSC - BSC compared to Interferon-beta1-aIM – DMF – BSC - BSC and in €32,998  for Glatiramer acetate – Fingolimod – BSC – BSC compared to Glatiramer acetate – DMF – BSC – BSC. The above estimates did not vary substantially across a range of assumptions investigated within the sensitivity analyses. CONCLUSIONS: The use of fingolimod as second-line treatment compared to DMF in patients with highly active relapsing-remitting MS in a Greek health care setting results in long-term clinical benefit and it is associated with a modest incremental cost-effectiveness ratio that most decision makers would consider acceptable especially for such a disabling disease.