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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, ALFFratio, 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. ALFFratio 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 ALFFratio 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. The amplitude of low‐frequency fluctuation (ALFF) was measured at the beginning of hospitalization. Baseline regional activity of the brain seems to be able to predict early response to treatment for schizophrenia. [ABSTRACT FROM AUTHOR]