Risk scores used in early warning systems exist for general inpatients and patients with suspected infection outside the intensive care unit (ICU), but their relative performance is incompletely characterized. To compare the performance of tools used to determine points-based risk scores among all hospitalized patients, including those with and without suspected infection, for identifying those at risk for death and/or ICU transfer. In a cohort design, a retrospective analysis of prospectively collected data was conducted in 21 California and 7 Illinois hospitals between 2006 and 2018 among adult inpatients outside the ICU using points-based scores from 5 commonly used tools: National Early Warning Score (NEWS), Modified Early Warning Score (MEWS), Between the Flags (BTF), Quick Sequential Sepsis-Related Organ Failure Assessment (qSOFA), and Systemic Inflammatory Response Syndrome (SIRS). Data analysis was conducted from February 2019 to January 2020. Risk model discrimination was assessed in each state for predicting in-hospital mortality and the combined outcome of ICU transfer or mortality with area under the receiver operating characteristic curves (AUCs). Stratified analyses were also conducted based on suspected infection. The study included 773 477 hospitalized patients in California (mean [SD] age, 65.1 [17.6] years; 416 605 women [53.9%]) and 713 786 hospitalized patients in Illinois (mean [SD] age, 61.3 [19.9] years; 384 830 women [53.9%]). The NEWS exhibited the highest discrimination for mortality (AUC, 0.87; 95% CI, 0.87-0.87 in California vs AUC, 0.86; 95% CI, 0.85-0.86 in Illinois), followed by the MEWS (AUC, 0.83; 95% CI, 0.83-0.84 in California vs AUC, 0.84; 95% CI, 0.84-0.85 in Illinois), qSOFA (AUC, 0.78; 95% CI, 0.78-0.79 in California vs AUC, 0.78; 95% CI, 0.77-0.78 in Illinois), SIRS (AUC, 0.76; 95% CI, 0.76-0.76 in California vs AUC, 0.76; 95% CI, 0.75-0.76 in Illinois), and BTF (AUC, 0.73; 95% CI, 0.73-0.73 in California vs AUC, 0.74; 95% CI, 0.73-0.74 in Illinois). At specific decision thresholds, the NEWS outperformed the SIRS and qSOFA at all 28 hospitals either by reducing the percentage of at-risk patients who need to be screened by 5% to 20% or increasing the percentage of adverse outcomes identified by 3% to 25%. In all hospitalized patients evaluated in this study, including those meeting criteria for suspected infection, the NEWS appeared to display the highest discrimination. Our results suggest that, among commonly used points-based scoring systems, determining the NEWS for inpatient risk stratification could identify patients with and without infection at high risk of mortality.