Abstract Background Dysregulation of epigenetic processes might account for alterations of the hypothalamic-pituitary-adrenal axis observed in patients with schizophrenia. Therefore, in this study, we aimed to investigate methylation of the glucocorticoid receptor (NR3C1) gene in patients with schizophrenia-spectrum disorders, individuals at familial high risk of schizophrenia (FHR-P), and healthy controls with respect to clinical manifestation and a history of psychosocial stressors. Methods We recruited 40 first-episode psychosis patients, 45 acutely relapsed schizophrenia (SCZ-AR) patients, 39 FHR-P individuals, and 56 healthy controls. The level of methylation at 9 CpG sites of the NR3C1 gene was determined using pyrosequencing. Results The level of NR3C1 methylation was significantly lower in first-episode psychosis patients and significantly higher in SCZ-AR patients compared with other subgroups of participants. Individuals with FHR-P and healthy controls had similar levels of NR3C1 methylation. A history of adverse childhood experiences was associated with significantly lower NR3C1 methylation in all subgroups of participants. Higher methylation of the NR3C1 gene was related to worse performance of attention and immediate memory as well as lower level of general functioning in patients with psychosis. Conclusions Patients with schizophrenia-spectrum disorders show altered levels of NR3C1 methylation that are significantly lower in first-episode psychosis patients and significantly higher in SCZ-AR patients. Higher methylation of the NR3C1 gene might be related to cognitive impairment observed in this clinical population. The association between a history of adverse childhood experiences and lower NR3C1 methylation is not specific to patients with psychosis. Longitudinal studies are needed to establish causal mechanisms underlying these observations.