We previously showed that overexpression of IL-9 controls lung fibrosis induced by silica particles in mice (Arras and colleagues; Am J Respir Cell Mol Biol 2001;24:368–375). This protection was associated with an expansion of lung B lymphocytes. To explore the contribution of these cells in the protective effect of IL-9, we crossed IL-9 transgenic (IL-9+) and B-deficient (B−) mice. The antifibrotic effect of IL-9 was abolished in mice deficient in B lymphocytes (B−IL-9+) and restored by reconstituting these mice with B lymphocytes. The expression of the antifibrotic mediator prostaglandin (PG)E2 was markedly increased in the lung of IL-9+ mice at baseline, and similarly high levels were found in both wild-type and transgenic strains upon silica treatment. This PGE2 expression was completely abolished in B− mice, both at baseline and upon silica administration. In vitro, alveolar and peritoneal macrophages from IL-9+ mice had an increased capacity to produce PGE2 in response to LPS or silica. This capacity was markedly reduced in macrophages obtained from B− mice and restored by co-incubating macrophages with B lymphocytes from IL-9+ mice. The increased PGE2 response of IL-9+ macrophages was dependent on cyclooxygenase 2 expression, based on transcript analysis and inhibition by NS398. We conclude that B lymphocytes are essential for the protection against lung fibrosis and macrophage overexpression of PGE2 in IL-9 transgenic animals.