Objectives: The purpose of this study was to assess the safety and dynamics of the onset of antipyretic efficacy of intravenous (IV) acetaminophen versus oral (PO) acetaminophen in the treatment of endotoxin-induced fever.Methods: This randomized, double-blind, double-dummy, single-dose study was conducted at a single center in the United States in healthy volunteer adult males with an endotoxin-induced fever to assess the antipyretic efficacy and safety of IV acetaminophen 1 g versus PO acetaminophen 1 g over 6 hours. Subjects who achieved a sufficient fever response to a test dose of reference standard endotoxin were randomly assigned to receive either IV acetaminophen and PO placebo (n = 54) or PO acetaminophen and IV placebo (n = 51). The primary efficacy outcome was the weighted sum of temperature differences from baseline at time T0 through T120 minutes. Safety evaluations included adverse event (AE), physical exam, and laboratory assessments.Results: Of 105 subjects receiving study medication, 24 vomited within 2 hours postdose (PO acetaminophen, n = 15; and IV acetaminophen, n = 9) and were excluded from the modified intent-to-treat population that consisted of 36 and 45 subjects treated with PO and IV acetaminophen, respectively. While this was done to not confer an advantage to the IV formulation, a sensitivity analysis including these subjects did not change the overall efficacy results. Statistically significant results favoring IV acetaminophen were observed for the primary endpoint (weighted sum of temperature differences over 120 minutes, p = 0.0039) and also at each time point from T30 to T90 minutes, although the maximum mean observed temperature difference was only 0.3°C. The study drugs were well tolerated. The AE frequency was comparable between the IV and PO groups.