IntroductionLow self‐esteem is a frequent symptom in major depressive disorder (MDD). This functional magnetic resonance imaging study investigated whether MDD patients with low self‐esteem show a distinct neural pathophysiology. Previous studies linked low self‐esteem to reduced task‐induced deactivation of the pregenual anterior cingulate cortex (pgACC) as a part of the default mode network, and to reduced connectivity between pgACC and reward system. Goya‐Maldonado et al. identified an MDD subtype with pgACC and ventral striatal overactivations during reward processing. We hypothesized that this subtype might be characterized by low self‐esteem.MethodsEighty‐three MDD patients performed the desire–reason dilemma task and completed the Rosenberg Self‐Esteem Scale (RSES). Brain activity during bottom‐up reward processing was regressed upon the RSES scores, controlling for depression severity measured by the Montgomery–Åsberg Depression Rating Scale. To corroborate the findings, we compared self‐esteem scores between patient subgroups with impaired task‐induced deactivation (n = 31) and with preserved task‐induced deactivation (n = 31) of the pgACC.ResultsConsistent with our a priori hypothesis, activity in a bilateral fronto‐striatal network including pgACC and ventral striatum correlated negatively with RSES scores, also when controlling for depression severity. In the additional analysis, patients with impaired task‐induced pgACC deactivation showed lower self‐esteem (t (52.82) = −2.27; p = .027, d = 0.58) compared to those with preserved task‐induced pgACC deactivation.ConclusionsWe conclude that low self‐esteem in MDD patients is linked to a task‐induced deactivation dysfunction of the pgACC. Our findings suggest that a previously described possible subtype of MDD with pgACC and ventral striatal overactivations during reward processing is clinically characterized by low self‐esteem.