To evaluate a minute-by-minute monitoring algorithm against a periodic early warning score (EWS) in detecting clinical deterioration and workload. Periodic EWSs suffer from large measurement intervals, causing late detection of deterioration. This might be prevented by continuous vital sign monitoring with a real-time algorithm such as the Visensia Safety Index (VSI). This prospective comparative data modeling cohort study (NCT04189653) compares continuous algorithmic alerts against periodic EWS in continuous monitored medical and surgical inpatients. We evaluated sensitivity, frequency, number of warnings needed to evaluate (NNE) and time of initial alert till escalation of care (EOC): Rapid Response Team activation, unplanned ICU admission, emergency surgery, or death. Also, the percentage of VSI alerting minutes was compared between patients with or without EOC. In 1529 admissions continuous VSI warned for 55% of EOC (95% CI: 45-64%) versus 51% (95% CI: 41-61%) by periodic EWS. NNE for VSI was 152 alerts per detected EOC (95% CI: 114-190) compared to 21 (95% CI: 17-28). It generated 0.99 warnings per day per patient compared to 0.13. Time from detection score till escalation was 8.3 hours (IQR: 2.6-24.8) with VSI versus 5.2 (IQR: 2.7-12.3) hours with EWS (P=0.074). The percentage of warning VSI minutes was higher in patients with EOC than in stable patients (2.36% vs 0.81%, P<0.001). Although sensitivity of detection was not significantly improved continuous vital sign monitoring shows potential for earlier alerts for deterioration compared to periodic EWS. A higher percentage of alerting minutes may indicate risk for deterioration.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10916-023-01954-z.