Interleukin‐15 (IL‐15) is a novel cytokine with actions similar to IL‐2 because of common receptor components. Although IL‐15 is expressed in colonic epithelial cells and may regulate epithelial cell function, its effects on these cells are not fully defined. We explored the regulatory effects of IL‐15 on IL‐8 and monocyte‐chemoattractant protein‐1 (MCP‐1) production in the colonic epithelial cell line Caco‐2 as well as in freshly isolated human colonic epithelial cells. IL‐15 was added to intestinal epithelial cells under various culture conditions. Levels of chemokines were determined by enzyme‐linked immunosorbent assay. To determine the elements of the IL‐2/IL‐15R complex involved we used neutralizing antibodies specific for individual receptor chains. IL‐15 down‐regulates IL‐8 and MCP‐1 production in Caco‐2 cells as well as in freshly isolated human colonic epithelial cells in a dose‐dependent manner. Intestinal epithelial cells became more responsive to IL‐15‐induced suppression when activated with greater IL‐1 doses. Strong chemokine suppression was seen when IL‐15 was given prior to, simultaneous with, or after stimulatory agent. Anti‐IL‐2Rγ antibodies efficiently blocked (82% inhibition) the suppression induced by IL‐15, while anti‐IL‐2Rβ antibodies were less effective. The involvement of β‐chain was further suggested by the finding that a mixture of both monoclonal antibodies (mAb) at a suboptimal concentration (1 µg/ml of each mAb) produced a synergistic inhibitory effect on down‐regulation of epithelial chemokine production. These results show that IL‐15 can suppress IL‐8 and MCP‐1 secretion by intestinal epithelial cells. A microenvironment containing high concentrations of IL‐15 may alter the recruitment of neutrophils to enterocytes at least partly by inhibiting IL‐8 and MCP‐1 production.