The effect of aspirin on whole blood cytokine production was studied in six healthy volunteers. Four days after cessation of a 3-day regimen of 650 mg of oral aspirin, there was a 70% increase in interferon-gamma (IFN-gamma) production, stimulated by a combination of interleukin-18 (IL-18) plus lipopolysaccharide (p < 0.05). At this time, there was a 4-fold increase in the production of tumor necrosis factor-alpha (TNF-alpha) compared to pre-aspirin levels (p < 0.03). TNF-alpha and IFN-gamma production returned to pre-aspirin levels one month after the discontinuation of aspirin. Short-term aspirin treatment induces a significant increase in the production of these cytokines, probably through inhibition of prostaglandins. These data suggest a novel pathway through which long aspirin use reduces the risk of colon cancer, and may explain the effects of aspirin in inflammatory bowel disease.