OBJECTIVES: To identify and explore how reimbursement decisions for natalizumab, a treatment for multiple sclerosis (MS), were overturned from an initial rejection to a recommendation. METHODS: This analysis was conducted in conjuntion with a wider review of the global reimbursement landscape for MS therapies. We reviewed reimbursement decisions or recommendations from global payer decision-making agencies, including any decisions where an initial rejection was overturned. We reviewed the agency rationale for both the original and subsequent decisions, and how the manufacturer influenced the decision reversal. RESULTS: Since 2006, 17 payer decisions for natalizumab were identified (six recommendations, eight restricted recommendations and three rejections). The three rejected decisions were later overturned by the manufacturer submitting further evidence. To PBAC this involved re-defining the indirect comparison to consider the heterogeneity in the trials included. To SMC and CADTH post-hoc analysis was submitted for the specific subgroup of rapidly evolving severe relapsing remitting MS. For CADTH a 15% price discount was agreed in addition. Across all agencies clinical need was an important factor.  CONCLUSIONS: By emphasising unmet needs, submitting further evidence in defined subgroups and ensuring indirect comparisons are methodologically sound, it has been possible to overturn initial negative decisions by payer agencies to restricted recommendations in define subgroup.  Identification of the optimum treatable population has proved pivotal in the reversal of fortune.