While serologic testing for ANA positivity is not universally used to screen for lupus, an argument could be made for ANA screening in the evaluation of atypical psychosis. Van Mierlo et al reported a point prevalence of ANA positivity in schizophrenia of 5.9-48.0% (5). In a study by Mantovani et al (6), 3 of 85 patients fulfilling Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for a first episode of primary psychotic disorder were found to be ANA positive; 2 of the 3 were also positive for anti-ribosomal P and anticardiolipin antibodies and met American College of Rheumatology classification criteria for SLE (7).The cases presented here illustrate that primary psychosis remains a diagnosis of exclusion, and nothing in the patient's previous history should override the clinical suspicion for a possible autoimmune etiology, especially if atypical psychosis features are present. In patients with atypical or treatment-refractory psychosis, imaging studies, broad assessment of serologic test results and cerebrospinal fluid markers of neuronal autoimmunity, as well as collaboration between rheumatologists and psychiatrists are all critical to establish a diagnosis of lupus psychosis.