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40% of colorectal cancer (CRC) patients undergoing curative resection of the primary tumor will develop metastases in the following years 1 . Therapies to prevent disease relapse remain an unmet medical need. Here we uncover the identity and features of the residual tumor cells responsible for CRC relapse. Analysis of single-cell transcriptomes of CRC patient samples revealed that the majority of poor prognosis genes are expressed by a unique tumor cell population that we named High Relapse Cells (HRCs). We established a human-like mouse model of microsatellite stable CRC that undergoes metastatic relapse following surgical resection of the primary tumor. Residual HRCs occult in mouse livers after primary CRC surgery gave rise to multiple cell types over time, including Lgr5+ stemlike tumor cells 2-4 , and caused overt metastatic disease. Using Emp1 (epithelial membrane Competitiveness (MINECO). HH is a Miguel Servet (CP14/00229) researcher funded by the

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