Abstract: Objective To explore the proliferative role of over-activated Notch1 signaling in renal cell carcinoma and the underlying mechanism. Methods The expression of Notch1 in 120 renal cell carcinoma (RCC) patients was evaluated immuohistochemically and compared with clinicopathological characteristics. RCC cell line ACHN was used in functional experiments to analyze the proliferative role of Notch1 signaling in renal cell carcinoma and its collaboration with PI3K/Akt pathway by Western blot. Results There were 64 cases of high expression of Notch1 in 120 cases of clear cell carcinoma of kidney tissue specimens. Higher expression of Notch1 was detected in larger tumors (diameter ≥7cm) compared with smaller ones(diameter <7cm) signifi cantly (P = 0.005), and was also detected in advanced tumors(TNM Ⅲ～Ⅳ stage) compared with localized ones(TNM Ⅰ～Ⅱ stage) insignificantly (P = 0.062). Conclusion Identification of the growth-promoting effect of Notch1 signaling and the underlying mechanism provides potential therapeutic targets for the treatment of RCC.