BACKGROUND: Chronic pain management includes treatment with the use of opioids, electrical stimulation and acupuncture. However, traditional understanding of chronic pain has recently been challenged in light of evidence supporting a key role of psycho-social factors and central sensitization in this population. Mindfulness-based stress reduction (MBSR), focuses on increasing awareness and acceptance of moment-to-moment experiences including difficult emotions and physical discomfort. OBJECTIVE: To examine the effects of a MBSR on chronic pain patients. DESIGN: A two-arm, blinding randomized controlled clinical trial with repeated-measures design. SETTING: One pain management clinic in a general hospital. PARTICIPANTS: Chronic pain patients (N = 149 patients). METHODS: The patients were randomly allocated to either psychoeducation (intervention group) or usual care (control group) (N = 75 vs 74 patients per group). The randomization was minimized, taking into account the imbalance between the groups over a number of prognostic clinical and demographic factors. The intervention included an 8-week MBSR program (2 hours per week) in a group format and the MBSR program was performed 2 times (1-2 months after enrollment and 7-8 months after enrollment). Study outcomes included Chronic pain (pain intensity and pain interference) assessed with Brief Pain Inventory (primary outcomes), and other secondary outcomes (i.e., quality of life, adherence to the intervention, mindfulness and self-awareness and drug assumption). We examined the differences at baseline (clinical-demographic data collected at enrollment), at 6 (T1) and 13 months (T2) between the intervention and control groups by means of chi-square and independent samples t tests. Normally distributed measurement data were represented by means and standard deviations. RESULTS: Participants in the intervention group revealed significantly greater reductions on impact of chronic pain in terms of pain intensity (worst pain in the last 24 hours, p < .001; pain right now, p < .001) and in terms of pain interference (interference with mood, p = .002; interference with normal work, p = .043; interference with relationship with other people, p = .036) at T1, and in terms of pain intensity (worst pain in the last 24 hours, p < .001; pain on average, p =. 013; pain right now, p < .001) and in terms of pain interference (interference with mood, p < .001; Interference with sleep, p < .001) at T2. A significant difference emerged in the perceived quality of life, between two groups at T2 (55.9 vs 58.7, t(133) = - 2.053, p = .044). CONCLUSIONS: Our study added values on the benefits of patients-focused MBSR to treatment of chronic pain. Future research can evaluate its long-term effects for patients of chronic pain with diverse socio-demographic and pain-related characteristics in a greater sample. REGISTRATION: Italian Clinical Trial Registry (NCT05843409). Recruitment: April 2023 to April 2024.