In light of concerns that not all medicines for ultra-rare (also known as ultra-orphan) conditions are appraised under the same NICE process, a new OHE Consulting Report discusses the distinct ethical and economic challenges faced by medicines for ultra-rare conditions, with particular reference to the challenges of HTA in the UK. A failure to consistently consider all ultra-rare disease medicines under the HST process could lead to inequalities in access and health outcomes for patients with ultra-rare conditions.