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Introduction: Treatment response at an early stage of schizophrenia is of considerable value with regard to future management of the disorder; however, there are currently no biomarkers that can inform physicians about the likelihood of response., Objects: We aim to develop and validate regional brain activity derived from functional magnetic resonance imaging (fMRI) as a potential signature to predict early treatment response in schizophrenia., Methods: Amplitude of low-frequency fluctuation (ALFF) was measured at the start of the first/single episode resulting in hospitalization. Inpatients were included in a principal dataset (n = 79) and a replication dataset (n = 44). Two groups of healthy controls (n = 87; n = 106) were also recruited for each dataset. The clinical response was assessed at discharge from the hospital. The predictive capacity of normalized ALFF in patients by healthy controls, ALFF ratio , was evaluated based on diagnostic tests and clinical correlates., Results: In the principal dataset, responders exhibited increased baseline ALFF in the left postcentral gyrus/inferior parietal lobule relative to non-responders. ALFF ratio of responders before treatment was significantly higher than that of non-responders (p < 0.001). The area under the receiver operating characteristic curve was 0.746 for baseline ALFF ratio to distinguish responders from non-responders, and the sensitivity, specificity, and accuracy were 72.7%, 68.6%, and 70.9%, respectively. Similar results were found in the independent replication dataset., Conclusions: Baseline regional activity of the brain seems to be predictive of early response to treatment for schizophrenia. This study shows that psycho-neuroimaging holds promise for influencing the clinical treatment and management of schizophrenia., (© 2019 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.)