Cullin-associated NEDD8-dissociated 1 (CAND1) plays a vital role in regulating the activity of Cullin-RING ubiquitin ligases (CRLs), which are frequently dysregulated in cancer. However, the role of CAND1 in hepatocellular carcinoma (HCC) remains unknown. Here, we found that CAND1 was overexpressed in HCC tissues compared to corresponding adjacent liver tissues (71.7% vs 16.7%); high expression of CAND1 was associated with poor overall survival (40.7 vs 57.3 months, P=0.0013); and CAND1 was an independent risk factor for the prognosis of HCC patients (N=138, P=0.018). Functional studies revealed that CAND1 knockdown efficiently suppressed the proliferation of liver cancer cells by activating caspase-8-dependent mitochondrial apoptosis. We also observed a mutual activation loop between caspase-8 and Receptor Interacting Protein 1 (RIP1), which amplified CAND1 knockdown-induced apoptotic signals in the cells. Furthermore, RIP1 inhibitor Necrostatin-1 eliminated the activation of caspase-8. In conclusion, our study pioneered in reporting high CAND1 expression as a predictor of poor prognosis for HCC patients. CAND1 silencing suppressed HCC cell proliferation by inducing caspase-8/RIP1-dependent apoptosis. These findings supported that CAND1 could be a new therapeutic target for liver cancer.