Introduction: Pulmonary fibrosis is characterized by progressive interstitial collagen deposition, leading to loss of function and death. Inflammation, chemokines and cytokines are though to precede and be relevant for collagen deposition. The effects of DF2162, a CXCR2 antagonist, on bleomycin-induced pulmonary fibrosis were studied here. Methods: C57BL/6J mice received an intra-tracheal instillation of 0.125U of BLEO or PBS. DF2162 (1.2 -30 mg/kg, BID) or vehicle were given orally. Results: Treatment with DF2162 inhibited PMN migration to BAL at days 2 and 8 after BLEO in a dose dependent manner. Maximal inhibition occurred at 6 mg/kg. DF2162 also reduced collagen deposition and decreased production of the fibrogenic cytokine IL-13 and CCL5. Despite reduced fibrosis and early neutrophil influx, there was a higher rate in DF-2162 (67%) - than in the vehicle-treated group (25%). Higher mortality was associated with accumulation of neutrophils, as assessed by MPO measurements, and diminished IL-10 levels in lung tissue. Conclusion: We suggest that the inhibition of neutrophil influx secondary to blockade of CXCR2 diminishes bleomycin-induced lung fibrosis. However, this is accompanied by a persistence of neutrophils in lung tissue and diminished production of regulatory cytokines, such as IL-10 and IL-13. As consequence, the lethality rate of treated animals is enhanced. These results suggest that chronic blockade of neutrophils may be deleterious in chronic pulmonary fibrosis.