OBJECTIVES: In the Netherlands, orphan drug developers can be exempted from providing a full pharmacoeconomic evaluation when applying for reimbursement, whereas in Scotland no such exceptions can be made. METHODS: All orphan drug reimbursement reports from the Dutch reimbursement institution (CFH) and guidance issued by the Scottish Medicines Consortium (SMC) were collected. RESULTS: 38 orphan drugs were submitted to the CFH; 37 to the SMC. Only one CFH submission included a full pharmacoeconomic evaluation, while almost all SMC submissions did. The CFH gave positive recommendations for reimbursement for 36 submissions (95%). In contrast, of the 37 SMC submissions, 19 (51%) received a positive recommendation for use. Half of the SMC submissions reported an unfavourable cost-effectiveness outcome; almost all of these received a negative recommendation. CONCLUSIONS: Differences in policies and requirements for submissions for orphan drugs can explain discrepancies in reimbursement and guidance for use decisions between Scotland and the Netherlands.