OBJECTIVES: Restricted protein diet (RPD) is only effective and safe treatment in patients with phenylketonuria (PKU) along with amino acids supplementation excluding phenylalanine. If untreated, PKU leads to severe mental retardation and wide range of other health complications. Although low-protein food for special medical purposes (LPF) is substantially more expensive than regular food, it is not reimbursed from public health insurance which may consequently lead to non-compliance. The main objective was to assess the cost-effectiveness of reimbursed RPD versus non-reimbursed RPD. METHODS: We developed a life-time Markov cohort cost-utility model with yearly cycle length and 3 health states, i.e. on diet (normal health), non-compliance to diet (mental retardation) and death. In order to estimate compliance to diet and dietary costs, we conducted our own cost-of-illness study (COI) including approximately half of Czech PKU patients. We assumed that reimbursement of basic LPF (flour, pasta etc.; €57.6/month) would decrease non-compliance from 34.1% (i.e. COI result) to 15% based on income distribution in society. Other probabilities (death) and utilities were derived from Czech mortality tables and literature. Costs and outcomes were discounted by 3%. Probabilistic sensitivity analysis (PSA) with 3000 iterations using a willingness-to-pay (WTP) threshold equal to 3-times GDP per capita (€47,000) in the Czech Republic was performed. RESULTS: Over a life-time horizon, reimbursed RPD compared to non-reimbursed RPD brings additional 0.81 QALY (23.16 vs. 22.35). The total life-time incremental costs are €16,235 (€16,235 vs. €0). ICER is thus equal to €19,955 per QALY gained. The results of PSA show that reimbursed RPD is cost-effective with probability of 95% at the WTP threshold. CONCLUSIONS: Reimbursed RPD proved its favourable cost-effectiveness in patients with PKU and therefore it represents good value for money. To our knowledge, this is the first cost-effectiveness analysis of RPD and it clearly shows a potential for cost-effective improvement in PKU patients.