Disease heterogeneity in patients with psychotic disorder may be explained by distinct profiles of premorbid adjustment. The current study explored premorbid adjustment profiles in patients with psychotic disorders, associations with cognitive and clinical characteristics after disease onset, and the role of familial factors. A total of 666 patients with psychosis (predominantly schizophrenia), 673 siblings, 575 parents, and 585 controls were included in this study. Cluster analyses were performed on the patients’ scores of the Premorbid Adjustment Scale (PAS), using information on domains (social, academic) and age epochs (childhood, early adolescence, late adolescence). Resulting profiles were compared with characteristics in patients and their unaffected relatives. Six clusters, labeled normal, social intermediate, academic decline, overall decline, overall intermediate, and overall impaired adjustment, were identified in patients. Patients in different clusters differed from each other on cognitive, clinical, and functional characteristics after disease onset. Heterogeneity in the patient population may be explained in part by the adjustment profile prior to disease onset. This is in line with theories that propose different etiologies in the development of psychosis. Patient profiles were expressed in unaffected siblings, suggesting a role for familial factors.