Acetaminophen (APAP) is often used as an analgesic and antipyretic during the inflammatory process. Its toxicity in overdoses depends on the integrity of the hepatic cytochrome P450 (CYP). The oxidative drug metabolism mediated by CYP can be inhibited during inflammatory diseases or after use of immuno-stimulants drugs and vaccines. The objective of this work was to evaluate if inflammation is able to modulate the toxicity of APAP. Five female Balb/c mice were injected subcutaneously with Freund Complete Adjuvant (FCA), and boosted with Freund’s Incomplete Adjuvant (FIA) at 14th day. Then, they were treated with 360 mg/kg of acetaminophen orally during the 14th, 15th and 16th days. Convenient control groups were included with APAP administration without immuno-stimulation. Serum levels of IL-1β, TNFα, IFNγ, α-1-acid glycoprotein (α-1-AGP), alanine transaminase (ALT), aspartic acid aminotransferase (AST), lactate dehydrogenase (LDH) and hepatic CYP2E1 expression were measured. Inoculation site of adjuvants and liver histopathological responses were also evaluated. FCA/FIA injection produced acute inflammatory response in the inoculation site and increased serum levels of the pro-inflammatory cytokines, α-1-AGP and LDH with reduction of hepatic CYP2E1 expression. A reduction of liver damage induced by APAP overdoses was also observed, suggesting that inflammatory processes can be protective against APAP hepatotoxicity.