Objective: To examine performance of a sepsis surveillance system in a simulated environment where modifications to parameters and settings for identification of at-risk patients can be explored in-depth. Materials and Methods: This was a multiple center observational cohort study. The study population comprised 14 917 adults hospitalized in 2016. An expert-driven rules algorithm was applied against 15.1 million data points to simulate a system with binary notification of sepsis events. Three system scenarios were examined: a scenario as derived from the second version of the Consensus Definitions for Sepsis and Septic Shock (SEP-2), the same scenario but without systolic blood pressure (SBP) decrease criteria (near SEP-2), and a conservative scenario with limited parameters. Patients identified by scenarios as being at-risk for sepsis were assessed for suspected infection. Multivariate binary logistic regression models estimated mortality risk among patients with suspected infection. Results: First, the SEP-2-based scenario had a hyperactive, unreliable parameter SBP decrease >40 mm Hg from baseline. Second, the near SEP-2 scenario demonstrated adequate reliability and sensitivity. Third, the conservative scenario had modestly higher reliability, but sensitivity degraded quickly. Parameters differed in predicting mortality risk and represented a substitution effect between scenarios. Discussion: Configuration of parameters and alert criteria have implications for patient identification and predicted outcomes. Conclusion: Performance of scenarios was associated with scenario design. A single hyperactive, unreliable parameter may negatively influence adoption of the system. A trade-off between modest improvements in alert reliability corresponded to a steep decline in condition sensitivity in scenarios explored.