AbstractSchizophrenia is a chronic brain disorder, and neuroimaging abnormalities have been reported in different stages of the illness for decades. However, when and how these brain abnormalities occur and evolve remains undetermined. We hypothesized structural and functional brain abnormalities progress throughout the illness course at different rates in schizophrenia. A total of 115 patients with schizophrenia were recruited and stratified into three groups of different illness periods: 5-year group (illness duration: ≤5 years), 15-year group (illness duration: 12–18 years), and 25-year group (illness duration: ≥25 years); 230 healthy controls were matched by age and sex to the three groups, respectively. All participants underwent resting-state MRI scanning. Each group of patients with schizophrenia was compared with the corresponding controls in terms of voxel-based morphometry (VBM), fractional anisotropy (FA), global functional connectivity density (gFCD), and sample entropy (SampEn) abnormalities. In the 5-year group we observed only SampEn abnormalities in the putamen. In the 15-year group, we observed VBM abnormalities in the insula and cingulate gyrus and gFCD abnormalities in the temporal cortex. In the 25-year group, we observed FA abnormalities in nearly all white matter tracts, and additional VBM and gFCD abnormalities in the frontal cortex and cerebellum. By using two structural and two functional MRI analysis methods, we demonstrated that individual functional abnormalities occur in limited brain areas initially, functional connectivity and gray matter density abnormalities ensue later in wider brain areas, and structural connectivity abnormalities involving almost all white matter tracts emerge in the third decade of the course in schizophrenia.