Background: Previous studies showed that connective tissue growth factor (CTGF)-induced proliferation of lung fibroblasts and production of chemokines in mesangial cells could be inhibited by lipoxin A₄ (LXA₄). It is speculated that LXA₄ could modulate the CTGF-induced epithelial to mesenchymal transition. Methods: The expressions of α-smooth muscle actin (α-SMA), E-cadherin, integrin-linked kinase (ILK), extracellular signal-regulated kinase 1/2 (ERK1/2), phosphatidylinositol 3-kinase (PI3-K), Akt and Smad signaling were assessed by Western blot and/or real-time RT-PCR, and activation of Ras or ILK by activity assay, expressions of α-SMA and zonula occludens-1 by immunofluorescence assay in proximal tubular epithelial cells (HK-2). Results: Pretreatment of HK-2 cells with LXA₄ inhibited the morphological fibroblast-like changes and α-SMA expression induced by CTGF but not by transforming growth factor-β₁ (TGF-β₁). The expressions of E-cadherin and zonula occludens-1 reduced by CTGF but not by TGF-β₁ were increased by LXA₄. LXA₄ inhibited the expression and activity of ILK and activation of Ras, ERK1/2, PI3-K and Akt in HK-2 cells stimulated by CTGF. LXA₄ did not affect TGF-β₁-induced expression of ILK, Smad-2/3 phosphorylation and Smad-2’s binding to Smad-4 and subsequent nuclear translocation. Conclusion: LXA₄ inhibits the tubular epithelial to mesenchymal transition, initiated by CTGF but not by TGF-β₁, via downregulation of ILK, Ras/MEK/ERK1/2 and PI3-K/Akt-dependent signal pathway stimulated by CTGF.