Purpose. The study aimed to investigate the effectiveness of antipyretic therapy on mortality in critically ill patients with sepsis requiring mechanical ventilation. Methods. In this study, we employed the multiparameter intelligent monitoring in intensive care II (MIMIC-II) database (version 2.6). All patients meeting the criteria for sepsis and also receiving mechanical ventilation treatment were included for analysis, all of whom suffer from fever or hyperthermia. Logistic regression model and R language (R version 3.2.3 2015-12-10) were used to explore the association of antipyretic therapy and mortality risk in critically ill patients with sepsis receiving mechanical ventilation treatment. Results. A total of 8,711 patients with mechanical ventilator were included in our analysis, and 1523 patients died. We did not find any significant difference in the proportion of patients receiving antipyretic medication between survivors and nonsurvivors (7.9% versus 7.4%, p = 0.49). External cooling was associated with increased risk of death (13.5% versus 9.5%, p < 0.001). In our regression model, antipyretic therapy was positively associated with mortality risk (odds ratio [OR]: 1.41, 95% CI: 1.20-1.66, p < 0.001). Conclusions. The use of antipyretic therapy is associated with increased risk of mortality in septic ICU patients requiring mechanical ventilation. External cooling may even be deleterious.