To delineate the mechanisms that facilitate leukocyte migration into the cystic fibrosis (CF) lung, expression of chemokines, including interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), and RANTES, was compared between CF and non-CF airway epithelia. The findings presented herein demonstrate that, under either basal conditions or tumor necrosis factor-α (TNF-α)- and/or interferon-γ (IFN-γ)-stimulated conditions, a consistent pattern of differences in the secretion of IL-8 and MCP-1 between CF and non- CF epithelial cells was not observed. In contrast, CF epithelial cells expressed no detectable RANTES protein or mRNA under basal conditions or when stimulated with TNF-α and/or IFN-γ (P ≤ 0.05), unlike their non-CF counterparts. Correction of the CF transmembrane conductance regulator (CFTR) defect in CF airway epithelial cells restored the induction of RANTES protein and mRNA by TNF-α in combination with IFN-γ (P ≤ 0.05) but had little effect on IL-8 or MCP-1 production compared with mock controls. Transfection studies utilizing RANTES promoter constructs suggested that CFTR activates the RANTES promoter via a nuclear factor-κB-mediated pathway. Together, these results suggest that 1) RANTES expression is altered in CF epithelia and 2) epithelial expression of RANTES, but not IL-8 or MCP-1, is dependent on CFTR.