OBJECTIVES: Rituximab (Rmb), Imatinib (Imt) and extra-corporeal photopheresis (ECP) are some of the strategies used as rescue therapy among patients with chronic graft-versus-host disease (cGVHD) who failes previous lines of treatment. The purpose of the study was to assess the cost-effectiveness of ECP in patients with cGVHD in Spain. METHODS: A Microsimulation model was built to estimate the clinical and economic consequences of ECP versus Rmb or Imt for 1000 hypothetical patients. Model probabilities concerning the efficacy of ECP, Rtm and Imt and severity degree per organ affected were obtained from literature. Treatment pathways and adverse events were evaluated taking into consideration expert opinion. Local data on costs (Euros 2010) and use of health resources were also validated by clinical experts. An annual 3% discount rate was applied to costs and outcomes. The perspective was the Spanish National Health System and time horizon was 5 years. RESULTS: Differences in improvement when ECP is used showed a gain at first year of 6.2% and of 6.7% against Rmb and Imt, respectively. The higher efficacy of ECP leads to a gain of 0.011–0.024 Quality Adjusted Life Year in the first year and 0.062-0.094 at year five compared to Rmb or Imt. Results showed than higher acquisition cost of ECP vs Imt was compensated at 9 months by higher efficacy and vs Rmb was partially compensated (517€ year 5). After 9 months, ECP was dominant vs Imt. The incremental cost-effectiveness ratio of ECP versus Rmb was 29,646€ per LY gained and 24,442 € per QALY gained at year 2.5. The probabilistic sensitivity analysis show robustness of results, being the ECP cost-effective in 70% of the simulated cases at year 5 (threshold of €30,000 per QALY gained). CONCLUSIONS: ECP as third-line therapy for cGVHD is a more cost-effective compared to Rmb or Imt.