OBJECTIVE: To investigate the effectiveness of mindfulness-based therapy (MT) and social support (SS) in patients with drug-resistant epilepsy. METHODS: We performed an assessor-blinded randomized control trial. Sixty patients with drug-resistant epilepsy were randomly allocated to MT or SS (30 per group). Each group received 4 biweekly intervention sessions. The primary outcome was the change in the total score of the Patient-Weighted Quality of Life in Epilepsy Inventory (QOLIE-31-P). Secondary outcomes included seizure frequency, mood symptoms, and neurocognitive functions. The assessors were blinded to the patient's intervention grouping. Results were analyzed using general linear model with repeated measure. RESULTS: Following intervention, both the MT (n=30) and SS (n=30) groups had an improved total QOLIE-31-P, with an improvement of +6.23 for MT (95% confidence interval [CI] +4.22 to +10.40) and +3.30 for SS (95% CI +1.03 to +5.58). Significantly more patients in the MT group had a clinically important improvement in QOLIE-31-P (+11.8 or above) compared to those who received SS (11 patients vs 4 patients). Significantly greater reduction in depressive and anxiety symptoms, seizure frequency, and improvement in delayed memory was observed in the MT group compared with the SS group. CONCLUSIONS: We found benefits of short-term psychotherapy on patients with drug-resistant epilepsy. Mindfulness therapy was associated with greater benefits than SS alone in quality of life, mood, seizure frequency, and verbal memory. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that mindfulness-based therapy significantly improves quality of life in patients with drug-resistant epilepsy.