BACKGROUND: Early detection of autoimmune psychosis (AP) mediated by antineuronal antibodies (Abs) is critical for achieving optimal clinical outcomes. However, evidence remains limited regarding who should be tested and how Ab-positive cases should be managed. In this large-scale study, we evaluated proposed clinical criteria for targeted Ab testing in psychiatric services and described the clinical course of seropositive patients. METHODS: Individuals with early psychosis (EP) or persistent psychosis (PP) were prospectively assessed with clinical criteria to determine high- or low-risk status for AP. Blood samples were collected for Ab testing using a fixed cell-based assay. Seropositive individuals were invited for detailed review, including clinical, functional, and cognitive assessments at baseline and a 12-month follow-up. Blood samples were collected from 754 individuals (EP: n = 352, PP: n = 402). RESULTS: Abs were present in 2.3% (17/754), including 3.4% (12/352) of patients with EP and 1.2% (5/402) of patients with PP. AP was confirmed in 2 cerebrospinal fluid (CSF)-positive high-risk individuals (total: 2/754, 0.3%; EP: 1/352, 0.3%; PP: 1/402, 0.2%). Both improved with immunotherapy. Although some low-risk patients were seropositive, none were diagnosed clinically with AP. CONCLUSIONS: AP prevalence was low in this cohort. Targeted testing informed by clinical high-risk criteria successfully identified 2 immunotherapy-responsive AP cases. This approach appears feasible but requires further validation. People with psychosis and high-risk AP features should be considered for Ab testing in sera and CSF where indicated. Further research is required to embed targeted Ab testing into mental health services.