BACKGROUND: Schizophrenia and related disorders (SRD) are characterized by positive and negative symptoms, such as anhedonia and avolition. There are no current FDA approved treatments for negative symptoms, which is a critical gap in our treatment of people with SRDs, since they are a major determinant of functional impairment. An emerging literature suggests that SRDs have a relationship with immune function and inflammation. Recently an SRD subgroup with high inflammation and elevated levels of anti-gliadin antibodies (AGA) of immunoglobulin G type (IgG) has been characterized. Negative symptom improvement has been previously observed with gluten removal in this subgroup in two small clinical trials. METHODS: We conducted a 5-week confirmatory double-blind placebo-controlled trial of a gluten free diet (GFD) versus gluten-containing diet (GCD) for negative symptoms in people with SRD who have elevated AGA IgG (NCT03183609). Participants were between the ages of 18-64 years, had baseline negative symptoms and a diagnosis of schizophrenia or schizoaffective disorder. Those included were screened for an AGA IgG >20 U, no serologic evidence of celiac disease, and stable antipsychotic treatment and dose. All participants were inpatients, received a GFD and were randomized to 30 grams of gluten or rice flour daily delivered in protein shakes. The Clinical Assessment Interview for Negative Symptoms (CAINS) Motivation and Pleasure (MAP) scale was the primary outcome measure. We also examined the CAINS Expressivity (EXP) scale, the Scale for the Assessment of Negative Symptoms (SANS), the Brief Psychiatric Rating Scale (BPRS), the MATRICS Consensus Cognitive Battery (MCCB) and conducted regular side effect screening and laboratory measures for safety. FINDINGS: Between 2018 and 2024, we included 39 participants (N=21 GFD and N=18 GCD). There was a significant improvement over time in the CAINS MAP (treatment X time df=30.1, F=2.78, p=0.045) in the GFD compared to GCD, but no significant change in the CAINS EXP, the SANS, BPRS or MCCB. The diet was well tolerated; the most frequently occurring side effects were constipation (38.1% GFD, 33.3% GCD), sedation (33.3% GFD, 50% GCD), dry mouth (33.3% GFD, 33.3% GCD), headache (33.3% GFD, 27.8% GCD), and insomnia (33.3% GFD, 27.8% GCD). INTERPRETATION: This is the first large scale double-blind randomized clinical trial in SRD with AGA IgG+. This replication of smaller studies suggests that negative symptoms, particularly anhedonia and avolition may be improved. However, we did not replicate our previous finding of cognitive improvement and COVID-19 likely impacted the extent of improvement in negative symptoms due to quarantines and lockdowns. More work is needed to determine the mechanism of action of gluten removal in this subgroup with hopes of developing new treatment targets for motivational deficits of this illness. FUNDING: This project was funded by NIMH R01 R01MH113617 (DL Kelly PI).