OBJECTIVES:  NICE and the SMC have different criteria, methodologies and implementation processes for appraising pharmaceutical products in the UK. However, both are established HTA bodies which utilise a cost per QALY threshold as a central element in decision-making. The objective of the study was to explore the differences and similarities between SMC and NICE decision-making, and where different recommendations result, to ascertain the reasons for these differences. METHODS:  We reviewed a total of 184 SMC decisions published between January 2013 and May 2016. 54 were not recommended due to a non-submission and so were not reviewed further. Where the product involved a resubmission (10 in total), the result of the resubmission was assumed to supersede the earlier “not recommended” advice. The remaining published decisions were then cross-referenced to the relevant NICE Single Technology Appraisal (STA) or Highly Specialised Technology (HST) guidance. RESULTS:  After applying the exclusion criteria, 120 decisions were analysed, of which 18 (~15%) resulted in substantively different recommendations between NICE and the SMC. All 18 involved full submissions to the SMC. NICE recommended products in 15 of the 18 decisions, while the SMC rejected 10 of the 18. 3 of the 10 products rejected by the SMC have all been recommended under the NICE HST process for highly specialised technologies. CONCLUSIONS:  The study results show that NICE and SMC decision-making is broadly aligned, but that substantively different recommendations can result for products licensed for specialised, rare or orphan indications. Through the HST programme, NICE currently has more flexibility in its decision-making methodology to recommend highly-specialised, ultra-orphan technologies than the SMC, which has no equivalent process. The results also highlight the challenges of applying PACE, disease modifiers and end of life criteria to products that blur the lines of orphan/ultra-orphan definitions or are targeted at niche therapy areas.