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OBJECTIVES: Evidence-based clinical practice guidelines (CPGs) for the treatment of pneumonia and sepsis have existed for many years with multiple studies suggesting improved patient outcomes. Despite their importance, little is known about variation in emergency department (ED) adherence to these CPGs. Our objectives were to estimate variation in ED adherence across CPGs for pneumonia and sepsis and identify patient, provider, and environmental factors associated with adherence. METHODS: This was a multicenter retrospective study using standard medical record review methods. The population consisted of consecutive adults hospitalized for pneumonia or sepsis (identified by discharge ICD-9 codes) at five Colorado hospitals (two academic, three community) who were admitted to the hospital from the ED and for whom the ED diagnosed or initiated treatment. The outcome measured was ED adherence to the CPG (primary) and in-hospital mortality (secondary). Hierarchical generalized linear models were used for analysis. RESULTS: Among 827 patients, ED care was 57% adherence to CPGs with significant variation in adherence across CPGs (sepsis 50%, pneumonia 64%, p < 0.001). Patients were less likely to receive adherent care if they presented with chief complaints that were associated but not typical of the diagnosis (odds ratio [OR] = 0.6, 95% confidence interval [CI] = 0.4–0.8), received an ED diagnosis that was not specific to the CPG (associated diagnosis OR = 0.3 [95% CI = 0.2–0.5]; unrelated diagnosis OR = 0.4 [95% CI = 0.2–0.6]) or presented to a community hospital (OR = 0.6,95% CI = 0.4–0.9). ED CPG nonadherence was associated with higher in-hospital mortality (OR = 2.4, 95% CI = 1.2–4.8). CONCLUSION: Adherence to ED infectious CPGs for pneumonia and sepsis varies significantly across diseases and types of institutions with significant room for improvement, especially in light of a significant association with in-hospital mortality.