Study Objectives: Medical comorbidities, including diabetes mellitus, hypertension, congestive heart failure, ischemic heart disease, malignancy, end-stage renal disease (ESRD), and chronic obstructive pulmonary disease (COPD) are known to influence the body's immune response to infection. However, the effect of patient comorbidities on the development of sepsis and mortality rates for "pre-shock" septic patients are not well understood.Methods: We performed a retrospective review of consecutive adult (>18 years old) patients diagnosed with sepsis in the emergency department (ED) and with initial (< 3 hours from presentation) "pre-shock" lactate values (2-4 mmol/L) presenting to two urban academic EDs from January 2010 to March 2015. Patient demographics, vital signs, laboratory values, comorbidities, medications, length of ED and hospital stay, and outcomes (including in-hospital mortality) were obtained. Descriptive data analysis and group-wise comparisons were performed.Results: A total of 407 patients were enrolled. Mean age was 65 years (SD 17.3) and 43% (175/407) were female. The overall mortality rate in this cohort was 20% (81/407). We found that COPD, ESRD, and malignancy correlated most with inhospital mortality. 19.7% (80/407) of patients had COPD, with prevalence significantly higher (p¼0.0270) among those who died (28.4% vs 17.5%). Additionally, 11.8% (48/407) of patients had ESRD, and the prevalence was significantly higher (p¼0.0370) among those who died (18.5% vs 10.2%). 7.6% (31/ 407) of patients had malignancy, and the prevalence was significantly higher (p¼0.0064) among those who died (14.8% vs 5.8%). Hypertension, diabetes mellitus, ischemic heart disease, and congestive heart failure did not appear to correlate with mortality.Conclusion: In this data set, we found that COPD, ESRD, and malignancy were significantly associated with in-hospital mortality among pre-shock septic patients. Other measured comorbidities did not appear to be significantly correlated with mortality. Further study is needed, including larger data sets, to better illuminate the impact of medical comorbidities on mortality within this vulnerable population.