OBJECTIVES: NICE has a remit to compare new interventions to the current standard of care, which could include off-label medication. NICE must also make recommendations for new interventions within their current marketing authorisations. The objective was to assess how frequently NICE request off-label comparators and the implications of this. METHODS: The NICE single technology appraisal (STA) final scopes from 2010-12 were reviewed. All STAs in development (as of 13/06/12) that had not been discontinued and had a draft or final scope were also reviewed. Off-label comparators were identified as those that were being used outside their license according to the European Medicines Agency or the Electronic Medicines Compendium. RESULTS: Of 54 completed STAs reviewed, the scopes of 14 (25.9%) requested comparison to at least one off-label comparator. Of these, the manufacturer performed this comparison in half of the cases. When the manufacturer did compare to an off-label comparator, the new intervention was recommended in 4 cases. NICE rejected the other 3 cases for not being cost-effective, thereby indirectly recommending the off-label alternative. Where the manufacturer did not perform the comparison, NICE accepted this decision in 6 (85.7%) cases, but for the other case the ERG performed additional analysis and found the new intervention to not be cost-effective when placed ahead of the off-label drug in the treatment sequence. Again, NICE rejected the new intervention, and indirectly endorsed use of the off-label comparator. Of the 73 STAs in development, 15 (20.5%) scopes requested off-label comparators. CONCLUSIONS: NICE have rejected new interventions in favour of off-label comparators, and given the significant number of off-label comparators requested in ongoing appraisals they will likely have to face similar issues in the future. If a new intervention can only be recommended within its licence but its comparators can be indirectly recommended off-label, this poses equality questions.