The present study was designed to examine whether eicosapentaenoic acid (EPA) inhibits the production of basal or stimulated endothelin (ET)-1 by platelet-derived growth factor (PDGF)-BB or epidermal growth factor (EGF), and DNA synthesis in cultured bovine mesangial cells. PDGF-BB and EGF stimulated ET-1 secretion in a dose-dependent fashion in these cells. EPA (10–100 µ M) exhibited dose-related inhibition of PDGF-BB- and EGF-stimulated ET-1 secretion. EPA had no inhibitory effects on basal ET-1 secretion in these cells. Moreover, 50 µ M EPA significantly attenuated PDGF-BB- and EGF-stimulated [<sup>3</sup>H]thymidine incorporation into mesangial cells. Receptor-binding experiments showed that EPA competitively inhibited <sup>125</sup>I-PDGF-BB or <sup>125</sup>I-EGF binding to mesangial cell surface receptors. Scatchard analysis for PDGF-BB receptor or EGF receptor revealed a linear regression fit and one binding site. Pretreatment with 50 µ M EPA suppressed the number of maximum binding sites, but did not affect the K<sub>d</sub> values. These results indicate that EPA potentially inhibits mesangial cell ET-1 production, when stimulated by PDGF-BB or EGF. This inhibitory effect of EPA could be related to the attenuation of mesangial cell proliferation via inhibition of the binding of PDGF-BB or EGF to their receptors due to alteration of the physicochemical characteristics of the cell membrane.