Introduction Clozapine has proven to have a unique efficacy on treatment-resistant schizophrenia (TRS). Nevertheless, studies show that 47%-63% of clozapine-treated patients may fail to respond after around 12-years of treatment (CRS). Several augmentation strategies have been proven to be effective in CRS. Objectives Hereby, we present two clinical cases of CRS successfully managed with brexpiprazole augmentation. Methods A 48-year-old man without comorbid substance use, treated with clozapine-brexpiprazole augmentation, and a 20-year-old man with comorbid substance use, treated with clozapine-brexpiprazole combination and subsequently with twice-injection aripiprazole (TIA). They were administered with the following assessments at t0, t1-3 (first month), t4-8 (monthly until 6-month follow-up): CGI, BPRS, PANSS, CDSS, Craving VAS, BARS, BIS-11, HRS-A, MADRS, YMRS, AIMS. Results At 1-month follow-up, both patients showed a considerable improvement (respectively 75% and 55.9% reduction of PANSS total score). At 6-month follow-up, reached only with the first patient, we noticed a further improvement (an overall 37.5% reduction of PANSS total score from the baseline). Conclusions The present work is the first report describing combination treatment strategies with clozapine and brexpiprazole which appear to give promising results. Disclosure No significant relationships.