OBJECTIVES: EPP is an ultra-rare genetic disease resulting in protoporphyria IX tissue accumulation. Exposure to light (and UV) leads to phototoxicity, acute intolerable reactions and 2^nd degree burns of exposed skin. Afamelanotide was approved by the EMA under exceptional circumstances. Economic arguments for afamelanotide are being evaluated. METHODS: An Excel^® model was constructed using a lifetime time horizon, a societal perspective and discount rates of 3.5% p.a. for costs and benefits. EPP symptoms were quantified as mild, moderate or severe. The proportion of patients in each state was derived from trial based quality of life scores. Disability Adjusted Life Years (DALY) were used to quantify benefit in the base case, with proxy conditions used to generate results due to the lack of DALY weights in EPP. Preliminary SF-36 data from early clinical trials and for other ‘similar’ conditions were used to perform exploratory sensitivity analyses, with the result presented as Quality Adjusted Life Years (QALYs). Resource use patterns were based on clinical opinion/ trial data. Unit costs were taken from national databases. RESULTS: The base case lifetime DALYs averted via the use of afamelanotide was 1.87 and the Incremental Cost-Effectiveness Ratio (ICER) was £373,000 per DALY averted. When hereditary angioedema was used as a proximate condition the ICER was £401,000 per QALY gained. Differing proxy sources for DALY weights generated estimates of DALYs averted ranging from 0.72 to 2.50. Alternative sources for utility weights generated results ranging from £208,000 to £1.1M per QALY gained. The model showed sensitivity to the number and the cost of each dose. CONCLUSIONS: Novel therapies for rare diseases often require novel health economic approaches. Afamelanotide offers substantive lifetime benefit and a cost-effective option.