The Third International Consensus Definitions Task Force defined sepsis as “life-threatening organ dysfunction due to a dysregulated host response to infection.” The performance of clinical criteria for this sepsis definition is unknown. To evaluate the validity of clinical criteria to identify patients with suspected infection who are at risk of sepsis. Among 1.3 million electronic health record encounters from January 1, 2010, to December 31, 2012, at 12 hospitals in southwestern Pennsylvania, we identified those with suspected infection in whom to compare criteria. Confirmatory analyses were performed in 4 data sets of 706,399 out-of-hospital and hospital encounters at 165 US and non-US hospitals ranging from January 1, 2008, until December 31, 2013. Sequential [Sepsis-related] Organ Failure Assessment (SOFA) score, systemic inflammatory response syndrome (SIRS) criteria, Logistic Organ Dysfunction System (LODS) score, and a new model derived using multivariable logistic regression in a split sample, the quick Sequential [Sepsis-related] Organ Failure Assessment (qSOFA) score (range, 0-3 points, with 1 point each for systolic hypotension [?100 mm Hg], tachypnea [?22/min], or altered mentation). For construct validity, pairwise agreement was assessed. For predictive validity, the discrimination for outcomes (primary: in-hospital mortality; secondary: in-hospital mortality or intensive care unit [ICU] length of stay ?3 days) more common in sepsis than uncomplicated infection was determined. Results were expressed as the fold change in outcome over deciles of baseline risk of death and area under the receiver operating characteristic curve (AUROC). In the primary cohort, 148,907 encounters had suspected infection (n?=?74,453 derivation; n?=?74,454 validation), of whom 6347 (4%) died. Among ICU encounters in the validation cohort (n?=?7932 with suspected infection, of whom 1289 [16%] died), the predictive validity for in-hospital mortality was lower for SIRS (AUROC?=?0.64; 95% CI, 0.62-0.66) and qSOFA (AUROC?=?0.66; 95% CI, 0.64-0.68) vs SOFA (AUROC?=?0.74; 95% CI, 0.73-0.76; P?.001 for both) or LODS (AUROC?=?0.75; 95% CI, 0.73-0.76; P?.001 for both). Among non-ICU encounters in the validation cohort (n?=?66?522 with suspected infection, of whom 1886 [3%] died), qSOFA had predictive validity (AUROC?=?0.81; 95% CI, 0.80-0.82) that was greater than SOFA (AUROC?=?0.79; 95% CI, 0.78-0.80; P?.001) and SIRS (AUROC?=?0.76; 95% CI, 0.75-0.77; P?.001). Relative to qSOFA scores lower than 2, encounters with qSOFA scores of 2 or higher had a 3- to 14-fold increase in hospital mortality across baseline risk deciles. Findings were similar in external data sets and for the secondary outcome. Among ICU encounters with suspected infection, the predictive validity for in-hospital mortality of SOFA was not significantly different than the more complex LODS but was statistically greater than SIRS and qSOFA, supporting its use in clinical criteria for sepsis. Among encounters with suspected infection outside of the ICU, the predictive validity for in-hospital mortality of qSOFA was statistically greater than SOFA and SIRS, supporting its use as a prompt to consider possible sepsis.