Multiple studies indicate that neuroendocrine (NE) differentiation in prostate cancer (PC) contributes to androgen independent progression. Levels of chromogranin A (CgA), which is produced by NE cells, are increased in advanced PC. However, the mechanism by which high levels of circulating CgA contribute to PC progression is unknown. To examine the effects of CgA on PC cells, we first performed proliferation assays in the presence of recombinant CgA (rCgA) in LNCaP and C4-2 PC cells and found that rCgA increased cell proliferation in a dose and time-dependent manner. Neuroendocrine differentiated PC cells, also overexpress the antiapoptosis protein survivin. Therefore, we examined survivin expression in the presence of CgA in PC cells. Western blot analysis showed that survivin was significantly increased by rCgA and inhibited by an anti-CgA antibody in both LNCaP and C4-2 cells. Survivin expression is believed to be regulated by PI3K/Akt pathway. We next assessed the phosphorylation status of Akt and found that Akt phosphorylation was increased by treatment with rCgA. To determine if Akt phosphorylation is necessary for rCgA-induced survivin expression, we examined the effects of Akt, MEK and PKC inhibitors on CgA-induced survivin expression and found that survivin expression was reduced in the presence of Akt inhibitors, but not MEK or PKC inhibitors. Furthermore, in the presence of an Akt inhibitors or siRNA of survivin, CgA-enhanced proliferation of C4-2 and LNCaP cells significantly decreased. Taken together, our results demonstrate that CgA can increase PC cell survival through Akt-mediated survivin upregulation.