Neuroblastoma is a common childhood tumor derived from neural crest precursor cells. In the present study, we investigated the expression and function of embryonic stem cell-expressed Ras (ERas), a novel Ras family protein previously reported as the specific expression gene in embryonic stem cells (ES cells), in neuroblastoma cell lines. Our results showed that the expressions of ERas were detected in neuroblastoma cell lines by RT-PCR and Western blotting. Therefore, we transfected a full length ERas expression vector into the neuroblastoma cell line SH-SY5Y, which has weak endogenous expression of ERas, and obtained clones with higher levels of expression. Overexpression of ERas did not increase the growth rate of the ERas transfectants but promoted their transforming activity. The ERas transfectants were more resistant to all the chemotherapy agents than the parental cell line. The ability of ERas to rescue cells from the toxic effect of chemotherapeutic agents was inhibited by the phosphatidylinositol 3'-kinase (PI3K) inhibitor PD294002. These results show that the ERas/PI3K pathway may provide resistance to chemotherapy and promote transforming activity in neuroblastoma.