Objective To explore whether desmocollin 3(Dsc3) mediates follicle stimulating hormone(FSH)-induced ovarian epithelial cancer cell proliferation by activating EGFR/Akt signaling pathway, thereby promoting tumor growth. Methods Immunohistochemical staining was used to detect the expression of Dsc3 in ovarian tumor tissues; Western blotting analysis was used to detect Dsc3 protein expression in 6 ovarian tumor cell lines and immortalized ovarian epithelial cells, and Dsc3, EGFR expression after FSH treatment. After knock-down Dsc3 and EGFR expression by siRNA and after treatment with PI3K/Akt signaling pathway inhibitor, Western blotting analysis was used to detect the expression of Dsc3, EGFR, Akt and pAkt; MTT assay was used to determine cellular growth. Results (1) The positive expression rates of Dsc3 in ovarian cancer tissues and borderline ovarian tumor tissues were significantly higher than that in benign ovarian cyst tissues(P<0.05); and the positive rates were similar between the former two tissues. The expression of Dsc3 in some ovarian cancer cells, such as Hey and HO8910 and borderline ovarian tumor cells MCV152, was higher than that in immortalized ovarian epithelial cells (Moody).(2)FSH up-regulated expression of Dsc3 and EGFR in a dose- and time-dependent manner. (3) Inhibition of Dsc3 by RNA interference inhibited the expression of EGFR and pAkt, but not Akt. Inhibition of EGFR by RNA interference inhibited the expression of Dsc3 and pAkt, but not Akt. Inhibition of PI3K/Akt signaling pathway inhibited the expression of Dsc3 and pAkt, but not Akt. The above three methods could all reduce the regulation role of FSH for PI3K/Akt signaling pathway. (4) Inhibition of Dsc3, EGFR and PI3K/Akt signaling pathway could significantly reduce FSH-induced cell proliferation(P<0.05). Conclusion Dsc3 can mediate FSH-induced ovarian epithelial cancer cell proliferation by activating EGFR/Akt signaling pathway, and thereby promoting tumor growth.