Introduction <p>Orelabrutinib is a novel Bruton’s tyrosine kinase inhibitor with high selectivity and a favorable safety profile. Despite substantial benefits in chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) with orelabrutinib, real-world data remain scarce. This study aimed to evaluate the efficacy and safety of orelabrutinib regimens for CLL/SLL in a real-world setting.</p> Methods <p>Between June 1, 2018, and September 30, 2024, a total of 63 patients with CLL/SLL who received an orelabrutinib-based regimen were included in this retrospective study. Data on demographics and characteristics, treatment, outcomes, and safety were retrospectively collected and analyzed. Outcomes included overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety.</p> Results <p>Of the 63 included patients, 18 (28.6%) patients received orelabrutinib-based regimen as first-line therapy, 33 (52.4%) as second-line therapy, and 12 (19.0%) as third-line therapy. The ORR and DCR were 90.5% (57/63, 95% CI 80.4–96.4) and 96.8% (61/63, 95% CI: 89.0–99.6), respectively. Regarding different treatment lines, ORR was 94.4% (17/18) for first-line therapy, 93.9% (31/33) for second-line therapy, and 75.0% (9/12) for third-line therapy. At a median follow-up of 72.0&#xa0;months (range: 24.0–216.0), the median PFS and OS were not reached. The 36-month PFS rate was 80.7% (95% CI 61.4–100.0) and the 36-month OS rate was 85.5% (95% CI 67.4–100.0). Thirty-eight (60.3%) patients experienced at least one adverse event (AE) of any grade during orelabrutinib therapy, with no treatment-related deaths observed. Among the 31 patients previously treated with ibrutinib/zanubrutinib, AEs reported during prior therapy mostly resolved or improved in severity after switching to orelabrutinib.</p> Conclusion <p>Orelabrutinib was effective and well tolerated for patients with CLL/SLL, providing evidence of clinical benefit in real-world settings.</p>