OBJECTIVES: Many orphan drugs receive market authorisation, however an assessment of cost-effectiveness is usually required before these drugs can be reimbursed. Recent research has explored the differences between HTA bodies in their rates of acceptance/rejection of orphan drugs. The objective of this study was to consider the relative weight of economic and clinical reasons for rejecting orphan drug submissions to HTA agencies. METHODS: Six HTA websites (NICE, SMC, NCPE, CEDAC, PBAC, AWMSG) were searched for summary guidance on 71 licensed orphan drugs identified from a search of the Orphanet website. RESULTS: Of 53 total non-approved submissions, in 53% of cases a high ICER was reported in the summary of guidance as a reason for rejection. In about 30% of these cases, the high drug cost was specified as the driver of the high ICER. The lack of a robust economic case was mentioned in 45% of rejections. Limited evidence of clinical benefit was shown in 43% of cases. Other reasons included inadequate type or quality of clinical data (21%) and non-acceptance of clinical positioning (11%). In 45% of cases the rejections were largely due to economic reasons; 6% of cases were not accepted due primarily to clinical reasons and in 49% of rejections the criticisms related to both the economic and clinical evidence. Uncertainty in the evidence was reported as a problem in most negative recommendations. CONCLUSIONS: Only slightly over half of the orphan drug HTA submissions to these agencies are explicitly rejected primarily on the basis of a high ICER. Most HTA rejections are due to a combined lack of robust economic and clinical evidence. This suggests that collecting the right kind of data and presenting a solid case that accounts adequately for any uncertainty is at least as important as meeting trial endpoints and choosing an optimal price.