The chemokine regulated on activation normal T cells expressed and secreted (RANTES) has been implicated in eosinophil chemotaxis in asthma and allergic diseases, which are thought to be T helper (Th) type 2-dominated diseases. However, adoptive transfer of Th1 cells in mice upregulates RANTES gene expression in the lung, and increased RANTES expression has been documented in several Th1 cell-dominated conditions that are associated with neutrophilia. The in vivo role of RANTES in the pathogenesis of disease processes is not well understood. To determine the effect of RANTES expression alone in vivo, we generated transgenic mice that overexpress RANTES specifically in the lung in an inducible fashion. The airways of the transgenic mice overexpressing RANTES displayed a significant increase in neutrophil infiltration compared with that in control mice. The increased airway neutrophilia was also evident when the transgenic mice were tested in a murine model of allergic airway inflammation. RANTES expression also induced expression of the chemokine genes macrophage inflammatory protein-2, 10-kDa interferon-gamma-inducible protein, and monocyte chemoattractant protein-1 in the lungs of the transgenic mice. Our studies highlight a hitherto unappreciated role for RANTES in neutrophil trafficking during inflammation. Thus increased RANTES expression, as observed during respiratory viral infections, may play an important role in the associated neutrophilia and exacerbations of asthma.