We performed multi-region sampling and sequencing on 14 patients with HCC, collecting a total of 75 tumor samples with spatial information and molecular data. In addition, 21 matched adjacent liver samples were also collected. All samples were subjected to RNA sequencing (RNA-seq). RNA sequencing was performed on Illumina NovaSeq 6000 platform with 40M pair-end 150bp reads per sample. Whole-exome sequencing (WES) was performed on 36 samples from patients T10, T13 and T18 (n = 26) as well as adjacent non-tumor tissues (n = 10). Paired end, 150bp read-length sequencing was then performed on Illumina NovaSeq 6000 platform with a mean sequencing coverage of 100X. Raw sequencing data has been deposited at the National Omics Data Encyclopedia (NODE) under the accession code OEP002956 ( http://www.biosino.org/node/project/detail/OEP002956).