OBJECTIVE: Our aim was to assess cost-effectiveness of mindfulness-based cognitive therapy (MBCT) compared with enhanced usual care (EUC) in treating patients with persistent medically unexplained symptoms(MUS). METHODS: A full economic evaluation with a one year time horizon was performed from a societal perspective. Costs were assessed by prospective cost diaries. Health-related Quality of Life was measured using SF-6D. Outcomes were costs per Quality-Adjusted Life Year (QALY). Bootstrap simulations were performed to obtain mean costs, QALY scores and incremental cost-effectiveness ratios (ICERs). RESULTS: MBCT participants (n=55) had lower hospital costs and higher mental health care costs than patients who received EUC (n=41). Mean bootstrapped costs for MBCT were €6269, and €5617 for EUC (95% uncertainty interval for difference: -€1576; €2955). QALYs were 0.674 for MBCT and 0.663 for EUC. MBCT was on average more effective and more costly than EUC, resulting in an ICER of €56,637 per QALY gained. At a willingness to pay of €80,000 per QALY, the probability that MBCT is cost-effective is 57%. CONCLUSION: Total costs were not statistically significantly different between MBCT and EUC. However, MBCT seemed to cause a shift in the use of health care resources as mental health care costs were higher and hospital care costs lower in the MBCT condition. Due to the higher drop-out in the EUC condition the cost-effectiveness of MBCT might have been underestimated. The shift in health care use might lead to more effective care for patients with persistent MUS. The longer-term impact of MBCT for patients with persistent MUS needs to be further studied.