PurposeTo explore the optimal timing of locoregional therapy in patients with colorectal cancer (CRC) recurrence after radical resection and initially unresectable liver metastases but no other metastases and whether maintenance therapy should be performed after achieving no evidence of disease (NED).MethodsThis study was jointly carried out in six medical institutions in China to collect the clinical data of patients with primary CRC from January 2015 to December 2021. Research participants were identified according to the inclusion criteria of this study for statistical analysis of the clinical characteristics and recurrence time.Results625 patients CRC with metachronous initially unresectable liver metastases but no other metastases were enrolled. Multivariate analysis showed that the number of metastases in the liver and the time from the start of first-line chemotherapy to locoregional therapy significantly affected the progression-free survival (PFS, P < 0.05) following the first-line treatment, and continued maintenance therapy reduced the risk of tumor progression in the patients (P < 0.05). Furthermore, stratified analysis showed that the median PFS of patients with 3-5 metastases in the liver was maximized when the time from the start of first-line chemotherapy to locoregional therapy was 3-4 months. Patients with > 6 metastases in the liver should extend the duration between the start of first-line chemotherapy and locoregional therapy to more than four months. Similarly, with the significant increase in the number of metastases in the liver, subsequent maintenance therapy significantly extended the PFS of the patients.ConclusionsThe overall therapeutic plan in patients with CRC recurrence after radical resection and initially unresectable liver metastases but no other metastases should consider the individual patients' situations, especially the number of metastases in the liver at initial recurrence.