Introduction Track and trigger systems (TTSs) based on vital signs are implemented in hospitals worldwide to identify patients with clinical deterioration. TTSs may provide prognostic information but do not actively include clinical assessment, and their impact on severe adverse events remain uncertain. The demand for prospective, multicentre studies to demonstrate the effectiveness of TTSs has grown the last decade. Individual Early Warning Score (I-EWS) is a newly developed TTS with an aggregated score based on vital signs that can be adjusted according to the clinical assessment of the patient. The objective is to compare I-EWS with the existing National Early Warning Score (NEWS) algorithm regarding clinical outcomes and use of resources. Method and analysis In a prospective, multicentre, cluster-randomised, crossover, non-inferiority study. Eight hospitals are randomised to use either NEWS in combination with the Capital Region of Denmark NEWS Override System (CROS) or implement I-EWS for 6.5 months, followed by a crossover. Based on their clinical assessment, the nursing staff can adjust the aggregated score with a maximum of-4 or +6 points. We expect to include 150 000 unique patients. The primary endpoint is all-cause mortality at 30 days. Coprimary endpoint is the average number of times per day a patient is NEWS/I-EWS-scored, and secondary outcomes are all-cause mortality at 48 hours and at 7 days as well as length of stay. Ethics and dissemination The study was presented for the Regional Ethics committee who decided that no formal approval was needed according to Danish law (J.no. 1701733). The I-EWS study is a large prospective, randomised multicentre study that investigates the effect of integrating a clinical assessment performed by the nursing staff in a TTS, in a head-to-head comparison with the internationally used NEWS with the opportunity to use CROS.