Intrinsic activity of the brain during resting-state is not random and is currently discussed as a neural reflection of self-referential processing. Self-reference is typically reduced in schizophrenia as a disorder of the self while extensive self-attribution of, eg, negative thoughts is characteristic for major depression. However, a quantitative meta-analysis targeting the resting-state brain activity in both disorders is lacking. Here, we predict primarily abnormal resting-state activity in brain regions related to self-referential processing. By means of activation likelihood estimation (ALE) on functional magnetic resonance imaging and positron emission tomography studies, we investigated concurrence of hyperactivation and hypoactivation in resting-state measurements of schizophrenic and depressed patients compared with healthy controls. We found hypoactivation in ventromedial prefrontal cortex (vmPFC), left hippocampus, posterior cingulate cortex, lower precueus and the precuneus, and hyperactivation in bilateral lingual gyrus of schizophrenic patients. In major depression, we found hyperactivation in vmPFC, left ventral striatum, and left thalamus and hypoactivation in left postcentral gyrus, left fusiform gyrus, and left insula. An overall ALE analysis confirmed the proximity of hypoactivation in schizophrenia and hyperactivation in major depression in the vmPFC.The opposing resting-state activity in vmPFC for the 2 disorders is in line with the different expression of dysfunctional self-reference as core characteristics of schizophrenia and major depression. The vmPFC has previously been identified as a crucial area for self-referential processing and may represent a target to increase the diagnostic validity of resting-state activity for disorders with dysfunctions of the self.