Our previous study revealed that Vav3 oncogene and secretory phospholipase A2-IIa (sPLA2-IIa) are overexpressed in androgen-independent prostate cancer cells relative to their androgen-dependent counterparts and contribute to development of hormone refractory prostate cancer. Vav3 is a multiple function protein with both signaling molecule and coactivator activities. sPLA2-IIa is a downstream effector of HER/HER2-PI3K-Akt-NF-κB signaling and involved in inflammatory response and tumorigenesis. The aim of the current study was to determine whether Vav3 is involved in up-regulation of sPLA2-IIa expression, given that Vav3 signals in the HER/HER2-elicited pathway. Among 46 prostate cancer specimens examined, Vav3 and sPLA2-IIa are overexpressed in 48 and 83% human prostate cancers, respectively. Vav3 overexpression is significantly associated with a high level expression of sPLA2-IIa. In addition, significant Vav3 nuclear localization is observed in two prostate cancer specimens, supporting a coactivator activity in prostate cancer cells. Further analysis revealed that Vav3 up-regulates expression of the sPLA2-IIa gene at the transcriptional level via HER/HER2-PI3K-Akt-NF-κB signaling. These data revealed that Vav3 overexpression as an additional underlying mechanism contributes to elevated sPLA2-IIa expression in prostate cancer.