Existing data suggest that antipyretic medications may have deleterious effects on immune function and may increase mortality in human infection. This study was designed to evaluate the impact of antipyretic therapy on 28-day in-hospital mortality when administered early in the course of gram-negative severe sepsis or septic shock. This study was a single-center retrospective cohort study at a 1,111-bed academic medical center of all febrile patients with gram-negative bacteremia hospitalized with severe sepsis or septic shock (n = 278) between Jan 2002 and Feb 2008. Although the raw mortality was lower in the group that received an early antipyretic medication (22 vs. 35 %, p = 0.01), patients in the early antipyretic group had higher mean arterial pressure (58.0 vs. 52.7, p = 0.01) and higher 24-h T (max) (39.3 vs. 39.0, p < 0.01). Early antipyretic therapy was not significantly associated with 28-day in-hospital mortality (adjusted OR 0.55, 0.29-1.03) in a multivariable logistic regression model controlling for APACHE-II score, hypotension, pneumonia, surgery during hospitalization, persistent fever, and in-hospital dialysis. In conclusion, early antipyretic therapy is not associated with increased mortality.