The Full Outline of UnResponsiveness (FOUR) score assessment of consciousness replaces the Glasgow Coma Scale (GCS) verbal component with assessment of brainstem reflexes. A comprehensive overview studying the relationship between a patient's FOUR score and outcome is lacking. We aim to systematically review published literature reporting the relationship of FOUR score to outcome in adult patients with impaired consciousness. We systematically searched for records of relevant studies: CENTRAL, MEDLINE, EMBASE, Scopus, Web of Science, , and OpenGrey. Prospective, observational studies of patients with impaired consciousness were included where consciousness was assessed using FOUR score, and where the outcome in mortality or validated functional outcome scores was reported. Consensus-based screening and quality appraisal were performed. Outcome prognostication was synthesized narratively. Forty records (37 studies) were identified, with overall low ( n = 2), moderate ( n = 25), or high ( n = 13) risk of bias. There was significant heterogeneity in patient characteristics. FOUR score showed good to excellent prognostication of in-hospital mortality in most studies (area under curve [AUC], >0.80). It was good at predicting poor functional outcome (AUC, 0.80–0.90). There was some evidence that motor and eye components (also GCS components) had better prognostic ability than brainstem components. Overall, FOUR score relates closely to in-hospital mortality and poor functional outcome. More studies with standardized design are needed to better characterize it in different patient groups, confirm the differences between its four components, and compare it with the performance of GCS and its recently described derivative, the GCS-Pupils, which includes pupil response as a fourth component.