Background: Regorafenib improves progression-free survival (PFS) and overall survival (OS) in patients with refractory metastatic colorectal cancer (mCRC). As a multikinase inhibitor, regorafenib could regulate the immune microenvironment. We aimed to evaluate the efficacy and safety of regorafenib plus tislelizumab in patients with mCRC in a real-world setting. Methods: We retrospectively analyzed the efficacy and safety of patients with mCRC who received at least one cycle of regorafenib plus tislelizumab between Mar 10, 2021 and Dec 18, 2022 in the Affiliated Hospital of Jiangnan University. 33 patients were received regorafenib (80mg, po, qd, d1-21) every 4 weeks and tislelizumab (200mg, iv) every 3 weeks, until disease progression, intolerable toxicities, or physician/patient withdrawal. The safety and efficacy were assessed by investigators per CTCAE v5.0 and RECIST v1.1, respectively. Results: A total of 33 mCRC patients (19 male vs. 14 female, 5 second-line recipients vs. 20 third-line recipients vs. 7 fourth-line recipients vs. 1 unknown, average age of 62.6 years) were enrolled. Most patients had left-sided cancer (63.6%), liver metastases and lung metastases both occurred in 19 patients (57.6%). With a median follow-up of 6.77 months (range 0- 21.6), the objective response rate (ORR) and disease control rate (DCR) were 15.2% and 100%, with a median PFS of 12.97 months (95% CI, 9.07-NA). The median OS was 19.83 months (95%CI, 7.66-32.01). There was no significant difference in OS between patients with and without liver metastases, the mOS was 19.8 months (95%CI, 9.53-NA) vs. not reached (NR); P = 0.368. The incidence of grade 3/4 adverse events was 24.2%, the most common TRAEs of grade ≥3 were anemia (9.1%) and hyperbilirubinemia (9.1%). No new safety signals were identified. Conclusions: The combination of regorafenib and tislelizumab had a manageable safety profile and promising efficacy in mCRC patients. And this combined therapy needs further prospective studies to verify the outcomes.