OBJECTIVES: The understanding of the clinical meaningfulness of outcomes in schizophrenia is important to determine the value of new treatments for patients, caregivers, practitioners and payers. The aim of this research was to provide an overview of general concepts and methodologies applied to determine meaningfulness of endpoints, to describe how outcomes are measured in schizophrenia and how treatment success and clinical meaningfulness are defined in schizophrenia from a Health Technology Assessment (HTA) perspective. METHODS: We conducted a targeted literature search focusing on antipsychotic treatment and clinical meaningfulness of schizophrenia outcomes, a review of HTA submission guidelines, HTA reports in schizophrenia, a survey on individual country requirements in sixteen countries and an analogue analysis to identify payer definitions of clinical meaningful differences. RESULTS: No consistent approach exists from payers, or in the literature, to determine clinical meaningfulness in schizophrenia outcomes. Historically, payers have based their value assessments of antipsychotics on available clinical evidence using systematic literature reviews and meta-analyses. Most widely used efficacy endpoints in antipsychotic trials are changes in PANSS scores, BPRS and CGI (CGI-I and/or CGI-S). Payers noted considerable variation in the definition of clinical meaningfulness to determine treatment response (20%-60% change in PANSS or BPRS score from baseline). Payers recommend validity should be demonstrated for clinical relevance of change on these endpoints using anchors such as patient-reported, functional and global outcomes. Overall, payers suggest establishing a minimal clinically important difference (MCID) based on robust scientific criteria. Beyond the traditional clinical measures, payers would like to see complementary evidence on quality of life, patient satisfaction, family burden, resource utilization and hospitalization. CONCLUSIONS: Approaches to determine clinical meaningfulness in schizophrenia outcomes vary widely. Further research is needed to validate the meaningfulness of changes in commonly used clinical endpoints and generate additional payer relevant evidence on patient and caregiver burden.