Liver is the most common organ of colorectal cancer (CRC) metastasis, and hepatic metastasis (HM) is regulated by complex protein network. Hence, we initiated a proteomic survey to seek interrelated multiplex markers related with HM. A total of 34 unique differential proteins were identified in the primary tumor tissues from 14 CRC patients with/without HM. A differential protein cluster, consisting of 17 proteins throughout PI3K/AKT pathway, was deduced and validated by Western blot. A three-protein signature elicited from the protein cluster, phosphorylated IkappaBalpha, TNFalpha and MFAP3L, was detected by immunohistochemistry on 105 pairs of CRC and normal samples. The positive protein signature was specifically correlated with HM (P < 0.001), and classified the HM risk of CRC patients with high sensitivity (92.85 +/- 4.87%) and specificity (94.94 +/- 2.5%). The high-risk group had significantly decreased overall survival (P < 0.001). Furthermore, RKO and HT29, two colon cancer cells with different expression status of the protein signature, were used to construct the nude mouse model of HM. And the HM occurrence of RKO cell (4/5) was dramatically higher than that of HT29 cell (1/5). Therefore, the protein signature derived from PI3K/AKT pathway is likely a promising multiplex biomarker for HM of CRC.