Objective To investigate the relationship between chromosome 6p copy number alterations (CNAs) and postoperative intrahepatic recurrence of hepatocellular carcinoma (HCC);and to screen for the target genes in CNA(s).Methods Array comparative genomic hybridization (CGH) and expression arrays were used to detect CNAs and differences in gene expression, respectively.The associations between CNAs in 6p and HCC recurrence were analyzed using the log-rank test, the Kaplan-Meier curves and the Cox proportional hazards models on 66 patients who had been follow-up for 2.6 ～ 73.3 months.The differentially expression of genes in the potentially recurrence-related CNAs were further evaluated by the MannWhitney U test on 117 HCCs, which included 109 cases with paired array CGH and expression data.Results 6p CNAs were detected in 46 (69.7％) of the 66 HCCs.Of the 8 CNAs with the most frequent recurrence of over 20％ , a gain at 6p21.1 was independently associated with a 2.3-fold (95％ CI =1.1 ～ 5.1, P ＜ 0.05) increased risk for intrahepatic recurrence and with a more pronounced 3.3-fold (95％ CI =1.4 ～ 8.2, P ＜0.05) risk for early recurrence (≤ 1 year).A panel of 9 genes, including BYSL and RPL7L1 within the documented 6p21.1, were observed to be upregulated in HCCs with 6p21.1 gain when compared with HCCs without (all P ＜ 0.05).A high BYSL expression significantly correlated with a larger tumor size (＞ 6 cm), vascular invasion and advanced tumor stage (all P ＜ 0.05), and high RPL7L1 expression significantly correlated with vascular invasion and advanced tumor stage (all P ＜ 0.05).Conclusion A gain at 6p21.1 was an independently prognostic marker for intrahepatic recurrence of postoperative HCC, particular for early recurrence, and BYSL and RPL7L1 might be the target genes in the recurrence-related 6p21.1 gain.