Missed or delayed diagnosis of sepsis can lead to serious patient harm. This study used a Symptom-Disease Pair Analysis of Diagnostic Error (SPADE) “look-forward” analysis to measure potential misdiagnosis of sepsis in patients discharged from the emergency department (ED) with treat-and-release fluid and electrolyte disorders (FED) or altered mental status (AMS). FED and AMS were associated with a spike in sepsis hospitalizations in the 7-day period following the ED visit. The authors suggest SPADE could be used to compare sepsis diagnostic performance across institutions and regions; develop interventions for targeted subgroups; and update early warning systems for sepsis diagnosis.