BACKGROUND AND HYPOTHESIS: Probiotic augmentation offers a promising treatment for bipolar disorder (BD) and schizophrenia spectrum disorder (SSD). By targeting microbiome deviations, they may improve both gut and brain health. STUDY DESIGN: In this double-blind, randomized, placebo-controlled trial with the multi-strain probiotic formulation Ecologic BARRIER, we aimed to improve psychiatric and cognitive symptoms, intestinal permeability, and gastrointestinal symptoms in patients with BD or SSD. A total of 131 patients were randomized 1:1 to receive either the probiotic supplement (n = 67) or a placebo (n = 64) for 3 months, in addition to treatment-as-usual. The primary outcomes were symptom severity assessed by the Brief Psychiatric Rating Scale and cognitive functioning by the Brief Assessment of Cognition in Schizophrenia. STUDY RESULTS: No significant effect of probiotics was observed on psychiatric symptoms, but borderline significant improvement was observed in the cognition category of verbal memory (Linear Mixed Model (LMM) 0.33; adjusted P = .059). Probiotics beneficially affected markers of intestinal permeability and inflammation, including zonulin (LMMserum = -18.40; adjusted P = .002; LMMfecal = -10.47; adjusted P = .014) and alpha-1 antitrypsin (LMM 9.26; adjusted P = .025). Indigestion complaints significantly decreased in male participants in the probiotics group (LMM = -0.70; adjusted P = .010). Adverse events were similar between groups. CONCLUSIONS: Our study observed significant advantages of probiotics for gut health in BD and SSD, with excellent safety and tolerability. A borderline effect on verbal memory was also indicated. These results underscore the need for further research into microbiome-targeted interventions for patients with complex brain disorders.