<b><i>Background:</i></b> Deficits in emotion regulation skills are possible factors maintaining major depressive disorder (MDD). Therefore, the aim of the study was to test whether integrating a systematic emotion regulation training (ERT) enhances the efficacy of routine inpatient cognitive behavioral therapy (CBT) for MDD. <b><i>Methods:</i></b> In a prospective randomized controlled trial, 432 inpatients meeting criteria for MDD were assigned to receive either routine CBT or CBT enriched with an intense emotion regulation skills training (CBT-ERT). <b><i>Results:</i></b> Participants in the CBT-ERT condition demonstrated a significantly greater reduction in depression (response rates - CBT: 75.5%, CBT-ERT: 84.9%; remission rates - CBT: 51.1%, CBT-ERT: 65.1%). Moreover, CBT-ERT participants demonstrated a significantly greater reduction of negative affect, as well as a greater increase of well-being and emotion regulation skills particularly relevant for mental health. <b><i>Conclusions:</i></b> Integrating strategies that target emotion regulation skills improves the efficacy of CBT for MDD.