BackgroundColon cancer with liver metastases (CCLM) characterized by genetic heterogeneity is an evolutionary process leading to variations in response to selective pressure, but the underlying evolutionary models still remains unclear.MethodsTotal of 30 samples, including primary tumor and two to four matched liver metastases from 8 treatment-naïve patients with CCLM were collected, and subjected to whole-exome DNA sequencing. PyClone was used to calculate intra and inter-tumor heterogeneity, LICHeE was used to reconstruct the cancer phylogeny trees and investigate the subclonal composition.ResultsThe genetic differences were observed between primary and metastatic lesions, as well as among multiple metastases in all patients. The natural history models of colorectal cancer in each case were identified, including parallel, linear, and branching evolution. Liver metastases could originate from primary lesions or other metastases. Pathway and process enrichment analysis also showed obvious heterogeneity and enhancement of several molecular functions.ConclusionsOur data reveal the genetic and heterogeneity between primary and metastatic lesions, as well as among multiple metastases and provide genomic evidence for clonal heterogeneity for CCLM.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00535-023-01989-6.