BackgroundDialectical behavioral therapy (DBT) skills have become increasingly used to treat several psychiatric conditions, including major depressive disorder (MDD). The aim of the study was to investigate the efficacy of an intervention that combines emotion regulation and mindfulness skills of DBT to prevent depression relapse/recurrence. Methods A total of 75 individuals (79% females; mean age, 52 years) with a diagnosis of MDD in complete or partial remission were recruited. Participants were randomly allocated either to an intervention combining emotion regulation and mindfulness skills (ER + M group, n = 37) or to a psychoeducative program (n = 38). After the 10-week treatment period, participants were followed for 1 year. Analyses were run in per-protocol (PP) and intention-to-treat (ITT) samples. The primary outcome measure was time to depression relapse/recurrence. Results ER + M training was not more effective than the control intervention in preventing depression relapse. However, PP and ITT analyses showed that participants trained in ER + M presented a significant reduction in depressive symptoms and overall psychopathology. Based on the PP and ITT analyses, neither of the interventions were related with an increase in dispositional mindfulness. Conclusions More studies are needed to confirm the efficacy of ER + M to decrease depressive symptoms and overall psychopathology.