The increase of eukaryotic translation initiation factor 4E (eIF4E) expression is frequently observed in several types of cancer, making eIF4E an attractive anticancer drug target. However, the role of eIF4E in gastric cancer pathogenesis remains unclear. Perifosine is a bioavailable alkylphospholipid exhibiting antitumor activity in a series of cancer types. In this study, gastric cancer cell lines were selected to explore the role of eIF4E as a potential target for treating human gastric cancer. The expression of total eIF4E (T-eIF4E)and phosphorylated eIF4E (p-eIF4E) in gastric cancer samples was detected by immunohistochemical assay. RNA interference was used to silence eIF4E expression. Sulforhodamine B assay was performed to evaluate tumor cell viability. Colony formation assay was used to examine the effects of eIF4E small interfering RNA (siRNA) or perifosine on colony formation. The mRNA levels of eIF4E were analyzed by qRT-PCR and western blot analysis was carried out to evaluate the expression of Akt and eIF4E. The results showed that increased expression levels of T-eIF4E and p-eIF4E were found in gastric cancer tissues and cells. Reduced eIF4E expression blocked the proliferation of gastric cancer cells. Perifosine downregulated the T-eIF4E and p-eIF4E levels in a dose- and time-dependent manner; it also inhibited the growth of gastric cancer cells. Moreover, this inhibitory effect was significantly enhanced by the combination of eIF4E siRNA and perifosine treatments. Our results indicate that eIF4E gene silencing can inhibit tumor cell growth, and eIF4E can be developed as a promising therapeutic target for gastric cancer.