Amplification of 1q21 is the most frequent genetic alteration in human hepatocellular carcinoma (HCC), being detected in 58%‐78% of primary HCC cases by comparative genomic hybridization. Recently, we isolated a candidate oncogene, Amplified in Liver Cancer 1 (ALC1), from 1q21 by hybrid selection. Here we demonstrate that ALC1 was frequently amplified and overexpressed in HCC. ALC1‐transfected cells possessed a strong oncogenic ability, increasing the colony formation in soft agar and increasing the tumorigenicity in nude mice, which could be effectively suppressed by small interfering RNA against ALC1. Functional studies showed that overexpression of ALC1 could promote G1/S phase transition and inhibit apoptosis. Molecular studies revealed that the oncogenic function of ALC1 might be associated with its roles in promoting cell proliferation by down‐regulating p53 expression. Conclusion: These results suggest that ALC1 is the target oncogene within the 1q21 amplicon and plays a pivotal role in HCC pathogenesis. (HEPATOLOGY 2007.)