Oxaliplatin, a key agent used for managing metastatic colorectal cancer (mCRC), is often discontinued due to cumulative toxicity. Its reintroduction in later treatment lines remains a common clinical practice, despite the absence of robust prospective trials supporting this therapeutic strategy. This study aimed to evaluate the efficacy of oxaliplatin rechallenge in refractory mCRC and to identify patient characteristics predictive of improved outcomes with this approach. We retrospectively analyzed patients treated with oxaliplatin in the third- or fourth-line setting at Vall d'Hebron Hospital between 2015 and 2021. Outcomes included overall response rate (ORR), disease control rate (DCR), and median progression-free survival (PFS). Patients achieving median PFS >6 months were classified as best-responders. Factors affecting PFS were analyzed with a Cox regression model. Amplicon-seq analysis of 61 genes was carried out using Illumina technology. Of 735 patients receiving third- or fourth-line treatment, 102 (14%) received oxaliplatin retreatment (69% in third line; 31% in fourth line). Median PFS was 4.0 months (95% CI 3.29-5.03 months), with an ORR of 12% and DCR of 39%. Twenty-eight patients (27%) were best-responders. Predictors of efficacy included response to first-line oxaliplatin, planned oxaliplatin discontinuation, and an oxaliplatin-free interval of at least 22.0 months. No significant associations were identified between molecular alterations and prognostic subgroups. Oxaliplatin-based reintroduction therapy is a viable strategy in mCRC, particularly for patients with a favorable prior response and prolonged oxaliplatin-free intervals. However, identifying more precise biomarkers is essential to improve patient selection and maximize treatment efficacy.