We report a study of emotion self-regulation training in patients with major depressive disorder (MDD) using simultaneous real-time fMRI and EEG neurofeedback (rtfMRI-EEG-nf). Emotion-relevant target nf measures included fMRI activities of the left amygdala and left rACC, and frontal EEG asymmetries in the alpha and high-beta bands. MDD patients successfully learned to upregulate all four measures simultaneously using rtfMRI-EEG-nf during a happy emotion induction task. EEG-fMRI data analyses provided new insights into mechanisms of rtfMRI-EEG-nf. These findings may lead to development of more efficient neurotherapies for MDD.