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Objective:. The genomic landscapes of metastatic colorectal cancer (mCRC) have been extensively studied; however, the genetic mechanisms underlying the locoregional recurrence (LR) of CRC remain unclear. The objective of our study was to investigate genomic evolution during LR in CRC using high-throughput sequencing. Methods:. Twenty-three CRC patients with matched primary and LR tissues were recruited from Nanfang Hospital and Zhejiang Cancer Hospital between January 2011 and December 2018. The last date of follow-up was March 2020. Tissue samples were analyzed by whole-exome sequencing and the genomic profiles were depicted by single nucleotide variation, mutational signature, copy number variation, clonal architecture, and other features. The evolutionary process was speculated with comparison of the genetic variations between primary and LR lesions. The disseminating clusters from primary to LR lesions were identified by variant allele frequency dynamics. Furthermore, the early-recurrent biomarker was explored by comparing the indel signature between early- and late-recurrent patients. The study was approved by the Institutional Review Board of Nanfang Hospital of Southern Medical University (approval No. 2020010) on September 11, 2020. Results:. The results highlighted distinct origins of LR between patients with high microsatellite instability and microsatellite stability. LR lesions evolved independently in patients with high microsatellite instability, while LR lesions were highly clonally related to the primary lesions in patients with microsatellite stability. Late-acquired variations in LR lesions encompassed a wide range of driver genes involved in histone methylation, DNA replication, T cell activation, PDCD1 gain, and LMNA loss. Furthermore, clonal analysis of the disseminating cells identified a dominant polyclonal seeding pattern during LR. The indel signature ID4 was associated with significantly shorter disease-free survival in patients with relapsed CRC according to a public dataset. Conclusion:. These findings pose a challenge for the development of new approaches targeting the interactions of multiple clones in the establishment of LR and in terms of optimizing the clinical management of susceptible patients.