Background: Negative neurocognitive bias is a core feature of depression that is reversed by antidepressant drug treatment. However, it is unclear whether modulation of neurocognitive bias is a common mechanism of distinct biological treatments. This randomized controlled functional magnetic resonance imaging study explored the effects of a single electroconvulsive therapy session on self-referent emotional processing. Methods: Twenty-nine patients with treatment-resistant major depressive disorder were randomized to one active or sham electroconvulsive therapy session at the beginning of their electroconvulsive therapy course in a double-blind, between-groups design. The following day, patients were given a self-referential emotional word categorization test and a free recall test. This was followed by an incidental word recognition task during whole-brain functional magnetic resonance imaging at 3T. Mood was assessed at baseline, on the functional magnetic resonance imaging day, and after 6 electroconvulsive therapy sessions. Data were complete and analyzed for 25 patients (electroconvulsive therapy: n = 14, sham: n = 11). The functional magnetic resonance imaging data were analyzed using the FMRIB Software Library randomize algorithm, and the Threshold-Free Cluster Enhancement method was used to identify significant clusters (corrected at P < .05). Results: A single electroconvulsive therapy session had no effect on hippocampal activity during retrieval of emotional words. However, electroconvulsive therapy reduced the retrieval-specific neural response for positive words in the left frontopolar cortex. This effect occurred in the absence of differences between groups in behavioral performance or mood symptoms. Conclusions: The observed effect of electroconvulsive therapy on prefrontal response may reflect early facilitation of memory for positive self-referent information, which could contribute to improvements in depressive symptoms including feelings of self-worth with repeated treatments.