Objectives: The objective of this study was to compare mindfulness-based cognitive therapy (MBCT) with a psycho-educational control group designed to be structurally equivalent to the MBCT program but excluding the claimed “active ingredient” of MBCT (i.e., mindfulness meditation practice) for the treatment of patients with major depression (MD).Design: This was a randomized controlled trial. Location: The study was conducted at the Institute of Psychiatry, University of Bologna, Italy. Subjects: Patients who had MD and who did not achieve remission following at least 8 weeks of antidepressant treatment were considered for inclusion. Eligible subjects were randomized to receive MBCT or psycho-education and were prospectively followed for 8 weeks. Outcome measures: MD severity was assessed with the Hamilton Rating Scale for Depression (HAMD). Measures of anxiety, mindfulness, and quality of life, as measured with the Beck Anxiety Inventory, Mindfulness Attention and Awareness Scale, and the Psychological General Well-being Index (PGWBI), respectively, were also included. All assessments were performed at baseline, 4 weeks, and 8 weeks. Changes of psychologic variables over the study period were analyzed by means of the repeated-measures analysis of variance. Results: Of 29 screened subjects, 16 received MBCT or psycho-education. Both HAMD and PGWBI scores improved to a significantly higher extent in the MBCT group than in the psycho-educational control group. Conclusions: Although limited by a small sample size and the lack of follow-up measures, the results of this preliminary study suggest the superiority of MBCT over psycho-education for subjects who had MD and who did not achieve remission following antidepressant treatment.