BACKGROUND: The neuroanatomical substrate underlying Major Depressive Disorder (MDD) is incompletely understood. Recent reports have implicated the insular cortex. METHODS: Two cohorts of participants with MDD were tested. In the first MDD cohort, we used standardised facial expression recognition tasks. In the second cohort, we focused on facial disgust recognition, a function associated with the insular cortex. T1 weighted MR imaging was used in the second cohort to test the hypothesis of abnormal insular volume being associated with impaired disgust recognition. RESULTS: Disgust recognition was particularly impaired in both cohorts. In the second cohort, the magnitude of the disgust recognition deficit correlated with reduced insula grey matter volume. Exploring the idea of insula involvement in MDD further, we identified the insular cortex and the anterior cingulate cortex as key neural correlates of core symptoms, in that scores of 3 clinical scales (the Beck Depression Inventory, the Hamilton Depression Rating Scale, and the Snaith-Hamilton Pleasure Scale) correlated with grey matter volume in these structures. LIMITATIONS: MDD participants were clinically representative of specialist and academic psychiatric practice in the UK and presented with robust primary diagnoses; we did not exclude common co-morbidities such as anxiety and personality disorders. CONCLUSIONS: We propose that cognitive and emotional functions assumed to be associated with the insula are adversely affected in patients with MDD and that this may, therefore, represent the substrate for some core clinical features of MDD. Further exploration of the involvement of the insular cortex in MDD is warranted.