BACKGROUND: Patients with depression tend to process negative information with regard to the self (i.e. self-referential processing). A better understanding of the neural underpinnings of self-referential processing in patients with depression is clinically important as it can inform on potential treatment targets. METHOD: This fMRI study sought to study the neural correlates of self-referential processing in patients with chronic major depressive disorder (cMDD) (n=17) and non-patient controls (n=18) using a passive processing paradigm. Stimuli consisted of positive, negative, negative depression related and neutral personality trait words or non-words. Participants were instructed to indicate whether a presented word was an existing word or a non-word while undergoing an fMRI scan. Participants also completed an explicit and an implicit measure of positive and negative self-associations outside the scanner. RESULTS: Non-patient controls had relatively increased activity in the medial prefrontal cortex (mPFC) during processing of negative depression related vs. neutral words whereas patients with cMDD had relatively decreased activity. Non-patient controls had relatively increased dorsolateral prefrontal cortex (dlPFC) activity during processing of positive vs. neutral words whereas patients with cMDD had relatively decreased activity. Explicit but not implicit self-associations with depression related words were associated with neural activity in the mPFC and the dlPFC. LIMITATIONS: The study did not include a clinical control group and therefore the specificity of findings remains unknown. CONCLUSIONS: The distinct neural processing of emotional self-relevant stimuli in the mPFC and the dlPFC in patients with cMDD might represent an emotional blunting response towards negative self-relevant stimuli.