Cytosolic phospholipase A2alpha (cPLA2) plays an important role in the development of several inflammatory diseases. The aim of the present study is to determine whether inhibition of cPLA2 expression, using specific antisense oligonucleotides against cPLA2 (antisense), is efficient in reducing inflammation after its development. Two mouse models of inflammation were included in the study: thioglicolate peritonitis and collagen-induced arthritis (CIA). The antisense was found to be specific and efficient in inhibiting cPLA2 expression and NADPH oxidase activity ex vivo in peritoneal phagocytes. Immunoblotting and immunohistochemistry analysis showed a significant elevation in cPLA2 expression in the inflamed joints of collagen-induced arthritis mice localized in cell infiltrate, chondrocytes and the surrounding skin and skeletal muscle. Similarly, the cPLA2 metabolite, leukotriene B4, accumulated in the peritoneal cavity of mice with peritonitis. Inhibition of elevated cPLA2 expression after development of inflammation by intravenous administration of antisense resulted in a dramatic reduction in inflammation and a significant reduction in neutrophils recruitment to the site of inflammation in both mouse models of inflammation. Our results demonstrate the critical role of cPLA2 for the duration of inflammation and suggest that inhibition of cPLA2 expression by antisense oligonucleotides may serve as an efficient treatment of inflammatory diseases.