Acute pancreatitis (AP) is an inflammatory disease involving the production of different cytokines and chemokines, and is characterized by leukocyte infiltration. Since the chemokine receptor CCR5 and its ligands (the CC chemokines CCL3/MIP-1, CCL4/MIP-1 and CCL5/RANTES) regulate leukocyte chemotaxis and activation, we investigated the expression of CCR5 ligands and the role of CCR5 and its ligands in experimental AP in mice. AP was induced by hourly intraperitoneal injections of caerulein in CCR5-deficient (CCR5^-/-) or WT mice. Induction of AP by caerulein resulted in an early increase of pancreatic CCL2, CCL3 and CCL4 mRNA expression, while CCL5 mRNA expression occurred later. CCR5^-/- mice develop a more severe pancreatic injury than WT mice during caerulein-induced AP, as assessed by a more pronounced increase in serum amylases and lipases levels and by more severe pancreatic edema, inflammatory infiltrates (mainly neutrophils) and necrosis. CCR5^-/- mice also exhibited increased production of CCL2/MCP-1, CCL3/MIP-1 and CCL4/MIP-1 during the course of caerulein-induced AP. In vivo simultaneous neutralization of CC chemokines with monoclonal antibodies in CCR5^-/- mice reduced the severity of caerulein-induced AP, indicating a role of CC chemokines in exacerbating the course of AP in the absence of CCR5. Moreover, simultaneous neutralization of CCR5 ligands in WT mice also reduced the severity of caerulein-induced AP. In conclusion, lack of the chemokine receptor CCR5 exacerbates experimental caerulein-induced AP, and leads to increased levels of CC chemokines and a more pronounced pancreatic inflammatory infiltrate, suggesting that CCR5 expression can modulate severity of AP.