Stress-induced phosphoprotein 1 (STIP1) is an adaptor protein that bridges between HSP70 and HSP90 folding and a secretory protein which regulates malignant cell growth. However, the role of STIP1 in hepatocellular carcinoma (HCC) remains unknown. Here, we found high expression of STIP1 in tumors was associated with worse overall survival (413 vs 62.7 months, P < 0.001) in 231 HCC patients. STIP1 was overexpressed in HCC tissues compared to adjacent non-tumor liver tissue (64.9% vs 4.0% P < 0.001), and serum STIP1 levels of HCC patients were elevated compared to healthy controls (P < 0.001). Mechanistically, STIP1 promoted HCC growth through PI3K-AKT-dependent anti-apoptotic pathway. STIP1 mediated cell growth in an autocrine fashion, which could be suppressed either by neutralizing extracellular STIP1 or by knocking down intracellular STIP1. In xenograft mouse model, knockdown of STIP1 significantly reduced tumor growth (P < 0.001). In conclusion, STIP1 is upregulated in HCC and associated with poor clinical prognosis. Blocking STIP1 activity suppresses HCC cell growth, providing the rationale for STIP1 as a potential therapeutic target in HCC. (C) 2017 Published by Elsevier Inc.