OBJECTIVES: New health technologies are required to demonstrate clinical and cost-effectiveness before recommendation by the National Institute for Health and Care Excellence (NICE) for reimbursement in England; however, higher cost-effectiveness thresholds may be considered for orphan and end-of-life (EOL) therapies. To help inform future submissions, the incremental cost-effectiveness ratios (ICERs) of – and rationale behind – accepted NICE submissions for orphan and EOL therapies were assessed. METHODS: All NICE single technology appraisals from January 2009 to December 2014 were included in the analysis. The decision, rationale, and manufacturer’s ICER (including patient access scheme where applicable) for each submission were extracted. Appraisals were then assessed for meeting NICE EOL or European orphan drug criteria. Multiple technology appraisals, resubmissions, vaccination programmes, requests for advice, and submissions where an ICER could not be determined were excluded. RESULTS: Of 111 relevant NICE submissions, 12 met orphan drug criteria, 16 met EOL criteria and 4 met both. For orphan drugs, 8/12 (67%) were accepted, with a mean ICER of £33,725 for accepted submissions (range: £24,544 - 56,693). For EOL drugs, 12/16 (75%) were accepted, with a mean ICER of £40,906 for accepted submissions (range: £14,795-£62,829). This compared with an overall acceptance rate for non-orphan/EOL NICE submissions of 71/87 (82%), with a mean ICER of £15,303 for accepted submissions (range: £1,537-£35,208). Rationale for acceptance of orphan and EOL drug submissions included unmet therapeutic need, lack of alternative treatment options, and innovation. CONCLUSIONS: Based on the evidence, NICE’s decision threshold was significantly higher for orphan/EOL drugs than for others (p<0.001). However, the overall acceptance rate was lower, and restrictions to patient sub-populations as well as patient access schemes were often applied. Nevertheless, the incorporation of elements such as unmet need into the decision-making process makes high ICERs appropriate where there is strong evidence of demonstrable clinical benefit.