Objective: The present study was conducted to examine the effect of epidermal growth factor (EGF) on Pi uptake and its related signal pathways in the primary cultured renal proximal tubule cells (PTCs). Results: EGF (50 ng/ml) inhibited Pi uptake, a typical marker of Na<sup>+</sup>/phosphate cotransporter, in a time- and dose-dependent manner. EGF-induced inhibition of Pi uptake was blocked by AG1478 (an EGF receptor antagonist), genistein or herbimycin A (tyrosine kinase inhibitors) and also blocked by mepacrine (a phospholipase A<sub>2</sub> (PLA<sub>2</sub>) inhibitor) and AACOCF<sub>3 </sub>(a cPLA<sub>2</sub> inhibitor). EGF increased [<sup>3</sup>H]-arachidonic acid (AA) release, which was also blocked by AG1478, genistein or herbimycin. Furthermore, EGF-induced inhibition of Pi uptake was blocked by indomethacin (a cyclooxygenase inhibitor) and econazole (a cytochrome P-450 epoxygenase inhibitor), but not by NDGA (a lipoxygenase inhibitor). On the other hand, EGF-induced inhibition of Pi uptake was blocked by staurosporine, H-7, or bisindolylmaleimide I (PKC inhibitors), PD 98059 (a p44/42 MAPK inhibitor), but not by SB 203580 (a p38 MAPK inhibitor). EGF-induced increase of [<sup>3</sup>H]-AA release was blocked by PKC inhibitors and a p44/42 mitogen-activated protein kinase (MAPK) inhibitor, but not by a p38 MAPK inhibitor. In addition, a PKC inhibitor blocked EGF-induced phosphorylation of p44/42 MAPK. Conclusion: EGF inhibits Pi uptake via PKC-p44/42 MAPK-cPLA<sub>2</sub> pathway in the PTCs.