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Objective: Depression affects about 16% of the U.S. population over a lifetime. People with chronic diseases have especially high rates of comorbid depression; 32% to 48% of people with epilepsy experience depression. This study evaluated the efficacy of a mindfulness-based cognitive therapy intervention for preventing major depressive disorder (MDD) episodes in people with epilepsy. Method: Participants (n = 128) were adults from Georgia, Michigan, Texas, and Washington with epilepsy and mild/moderate depressive symptoms. The 8-session weekly Project UPLIFT intervention, based on mindfulness-based cognitive therapy, was group-delivered via Web or telephone. Using a randomized, controlled crossover design, participants were assigned to Project UPLIFT or a treatment-as-usual (TAU) waitlist and assessed at baseline, and after intervening in the intervention group (∼10 weeks) and in the TAU group (∼20 weeks). Assessments included valid self-report measures of depression and MDD, knowledge/skills, and satisfaction with life. Results: The incidence of MDD episodes (new or relapse) from baseline to interim assessment was significantly lower in the intervention condition (0.0%) than in TAU (10.7%). Depressive symptoms decreased significantly more in the intervention condition than in TAU; Web and telephone did not differ. Change in knowledge/skills mediated the effect, which persisted over the 10 weeks of follow-up. Knowledge/skills and life satisfaction increased significantly more in the intervention condition than in TAU. Conclusions: Distance delivery of group mindfulness-based cognitive therapy can prevent episodes of MDD, reduce symptoms of depression, and increase life satisfaction in people with epilepsy. This intervention is easily modified for persons with other chronic diseases and other disparity populations.