Major depressive disorder (MDD) is characterized by a heterogeneous course and identifying patients at risk for an unfavorable course is difficult. Neuroimaging studies may identify brain predictors of clinical course and may help to further unravel the neurobiological processes underlying an unfavorable course. We investigated whether brain activation during an emotional memory paradigm is associated with depressive course. To this end, we followed 74 MDD patients and 45 healthy controls (HCs) for 2 years. At baseline, participants performed an emotional word-encoding and -recognition task during functional magnetic resonance imaging. Activation patterns were compared between patients with fast remission (n=22), remission with recurrence (n=23), non-remission (n=29), and HCs. Additionally, linear relations of brain activation and time to remission during the follow-up period were investigated across patients. We observed that during encoding of negative words, non-remitters showed higher activation of the left insula than HCs. Groups also differed in activation of the right hippocampus and left amygdala during negative encoding, with a trend for higher activation in non-remitters compared with HCs. Furthermore, hippocampal activation during negative word encoding was significantly and positively correlated with time to remission, irrespective of illness severity. Our findings suggest that higher activation in the left insula could serve as a neural marker of a naturalistic non-remitting course, whereas higher hippocampal activation is associated with delayed remission. Longitudinal analyses should clarify whether abnormal activation progresses further as a function of time with depression or may serve as load-independent markers of MDD course.