OBJECTIVES: To assess the cost-effectiveness of tapentadol prolonged release compared to morphine, oxycodone, hydromorphone, transdermal buprenorphine [TDB], and transdermal fentanyl [TDF] for the treatment of severe chronic non-cancer pain in Belgium. METHODS: A one year Markov transition state model with 4-week cycles was built. Four health states were defined: ‘no withdrawal and no adverse events treated’, 'occurrence of adverse events (AEs) with need for medical treatment', 'withdrawal due to AEs', and ‘withdrawal due to lack of efficacy'. Patients who were lacking efficacy or had poor tolerability switched to an alternative 2nd line opioid (oxycodone, morphine, hydromorphone, TDB or TDF). 3rd line therapy was the absorbing state. Data regarding efficacy, tolerability and utility values (EQ-5D) were derived from clinical trials and published literature. Switch rates to 2nd line therapies and resource consumption were estimated by clinical experts. Costs were calculated from the healthcare payer perspective including patients’ co-payments as stated in the Belgium pharmacoeconomic guidelines. One-way, scenario, and probabilistic sensitivity analyses were conducted. RESULTS: Compared to oxycodone (direct comparison data), tapentadol had almost the same cost but higher effectiveness, resulting in the incremental cost-effectiveness ratio (ICER) of 6 EUR per QALY gained. The ICERs of tapentadol versus TDB, TDF, hydromorphone and morphine equaled to 2,407, 5,811, 19,852, and 23,182 EUR per QALY gained, respectively. In the univariate sensitivity analysis, resource consumption, probabilities and utilities were varied for ±50%, ±20% and ±10%, respectively. Conclusions about the cost-effectiveness of tapentadol remained robust, especially when compared to oxycodone, TDF and TDB, which account for ca. 90% of the total strong opioid market in Belgium. The ICER in these cases did not exceed 10,000 EUR per QALY gained. CONCLUSIONS: To improve pain relief and quality of life in patients with severe chronic pain tapentadol appears to be the favourable and cost-effective treatment option in Belgium.