How different regimens of nicotine administration and withdrawal affect systemic inflammation is largely unknown. We studied the effects of chronic and acute nicotine administration and of nicotine withdrawal on the outcome of aseptic and septic systemic inflammation. Male C57BL/6 mice were implanted with subcutaneous osmotic pumps (to deliver nicotine) and intrabrain telemetry probes (to measure temperature). Aseptic inflammation was induced by lipopolysaccharide (40 mg/kg, intraperitoneally); sepsis was induced by cecal ligation and puncture. The chronic nicotine administration group received nicotine (28 mg/kg/d) for 2 weeks before the induction of inflammation and continued receiving nicotine until the end of the experiment; the acute nicotine administration group received saline for 2 weeks and nicotine thereafter; the nicotine withdrawal group received nicotine for 2 weeks and saline thereafter; the no nicotine group was infused with saline throughout the experiment. Compared to no nicotine, the chronic nicotine administration did not affect survival in either model of inflammation, possibly due to the development of nicotine tolerance. The acute nicotine administration increased the survival rate in aseptic inflammation from 11 to 33% (possibly by suppressing inflammation), but worsened the outcome of sepsis (possibly because the suppression of inflammation promoted microbial proliferation). Oppositely to acute nicotine, nicotine withdrawal increased the survival rate in sepsis from 18 to 40%. The effects on survival were not due to changes in body temperature. We conclude that acute nicotine administration and nicotine withdrawal affect survival in systemic inflammation, and that these effects strongly depend on whether inflammation is aseptic or septic.