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Objectives: Among patients with suspected infection, a single measurement of the quick Sepsis-related Organ Failure Assessment has good predictive validity for sepsis, yet the increase in validity from repeated measurements is unknown. We sought to determine the incremental predictive validity for sepsis of repeated quick Sepsis-related Organ Failure Assessment measurements over 48 hours compared with the initial measurement., Design: Retrospective cohort study., Setting: Twelve hospitals in southwestern Pennsylvania in 2012., Patients: All adult medical and surgical encounters in the emergency department, hospital ward, postanesthesia care unit, and ICU., Interventions: None., Measurements and Main Results: Among 1.3 million adult encounters, we identified those with a first episode of suspected infection. Using the maximum quick Sepsis-related Organ Failure Assessment score in each 6-hour epoch from onset of suspected infection until 48 hours later, we characterized repeated quick Sepsis-related Organ Failure Assessment with: 1) summary measures (e.g., mean over 48 hr), 2) crude trajectory groups, and 3) group-based trajectory modeling. We measured the predictive validity of repeated quick Sepsis-related Organ Failure Assessment using incremental changes in the area under the receiver operating characteristic curve for in-hospital mortality beyond that of baseline risk (age, sex, race/ethnicity, and comorbidity). Of 37,591 encounters with suspected infection, 1,769 (4.7%) died before discharge. Both the mean quick Sepsis-related Organ Failure Assessment at 48 hours (area under the receiver operating characteristic, 0.86 [95% CI, 0.85-0.86]) and crude trajectory groups (area under the receiver operating characteristic, 0.83 [95% CI, 0.83-0.83]) improved predictive validity compared with initial quick Sepsis-related Organ Failure Assessment (area under the receiver operating characteristic, 0.79 [95% CI, 0.78-0.80]) (p < 0.001 for both). Group-based trajectory modeling found five trajectories (quick Sepsis-related Organ Failure Assessment always low, increasing, decreasing, moderate, and always high) with greater predictive validity than the initial measurement (area under the receiver operating characteristic, 0.85 [95% CI, 0.84-0.85]; p < 0.001)., Conclusions: Repeated measurements of quick Sepsis-related Organ Failure Assessment improve predictive validity for sepsis using in-hospital mortality compared with a single measurement of quick Sepsis-related Organ Failure Assessment at the time a clinician suspects infection.