669 Background: Nowadays the optimal treatment for mCRC beyond second line is still questioned. During last years, regorafenib and TAS-102 showed to improve survival compared to best supportive care in pts with refractory mCRC. Recently, some retrospective analyses compared the efficacy and safety of regorafenib and TAS-102 reporting no significant differences in survival and response outcomes. In real-world clinical practice, chemotherapy (CT) rechallenge is often considered for refractory mCRC. However, evidences regarding CT rechallenge is limited and no study has previously compared such approach with the recently approved antineoplastic agents in late lines. The aim of this study was to compare the efficacy between CT rechallenge and regorafenib in pts with refractory mCRC. Methods: This is a mono-institutional retrospective study. We compared the efficacy of FOLFOX rechallenge and regorafenib in pts with mCRC refractory to at least 2 lines of standard CT, treated at Fondazione Policlinico Universitario “A. Gemelli”-IRCCS between Jan-10 and Jan-18. The primary endpoint was OS. Secondary endpoints were RR and PFS. Results: One hundred thirty-one pts received regorafenib and 43 FOLFOX rechallenge. OS was significantly higher with FOLFOX rechallenge than it was with regorafenib (13 vs. 6 months; HR 0.67, 95% CI 0.33-0.66; p = 0.0002). PFS was significantly higher in the FOLFOX rechallenge group compared to the regorafenib group (5 vs. 3 months; HR 0.64, 95% CI 0.46-0.89; p = 0.0073). Accordingly, RR was better in pts receiving FOLFOX rechallenge compared to regorafenib (25 vs. 3%; Chi-square p < 0.0001). Conclusions: Our study, although retrospective and small-sized, compared for the first time to our knowledge the efficacy of CT rechallenge to regorafenib in refractory mCRC. In our analysis, CT rechallenge with FOLFOX proved to be superior compared to regorafenib, with a survival and response benefit in pretreated mCRC. The survival benefit observed for rechallenge might be explained by the significantly higher tumor shrinkage achieved with CT rechallenge compared to regorafenib. Our results warrant further confirmation in wider and/or prospective analyses.