Background: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease. Recently, based on in-depth genomic analysis, new taxonomies for DLBCL have been proposed. Genetic subtype MCD is predominantly enriched with B-cell receptor-dependent NF-κB activation and well responded to Bruton’s tyrosine kinase (BTK) inhibitors. Ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) proved the efficacy in patients with MCD DLBCL in PHOENIX study. Orelabrutinib is a novel BTK inhibitor with excellent target selectivity. This study aimed to evaluate the efficacy and safety of orelabrutinib-containing regimens for the treatment of patients with MCD DLBCL in a real-world setting. Methods: Eligible patients with pathologically confirmed MCD DLBCL, regardless previous treatment, were included from 6 centers between January and December 2021. All patients received orelabrutinib-containing regimens and underwent at least one treatment response evaluation. Patients with known CNS lymphoma and primary mediastinal lymphoma were excluded. The primary endpoint was complete response rate (CRR) assessed by investigator using PET-CT per the 2014 Lugano Response Criteria for Non-Hodgkin Lymphoma. Safety was assessed by adverse events (AEs) referring to Common Terminology Criteria for AEs version 5.0. Results: Fourteen patients (10 males) were included. The median age was 66 (range 45-77) years, and 35.71% (5/14) documented ≥2 extranodal involved sites. Most patients had an Eastern Cooperative Oncology Group score of 0-1 (9/14, 64.29%), Ann Arbor Stage III-IV disease (11/14, 78.57%), elevated lactate dehydrogenase (9/14, 64.29%), and International Prognostic Index score ≥3 (8/14, 57.14%). All patients received orelabrutinib 150 mg once daily. Among them, 8 (57.14%) were treated with R-CHOP or rituximab plus etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin (R-EPOCH) as first-line therapy, and 6 (42.86%) with rituximab plus ifosfamide, carboplatin and etoposide (R-ICE), R-CHOP or rituximab with lenalidomide as second-line therapy. The CRR for the first-line and second-line therapy were 75.00% and 66.67%, respectively. The most common AEs were hematologic (platelet count decrease, white blood count decrease or lymphocyte count decrease), and non-hematologic AE was infection (urinary or respiratory). Reported AEs were generally manageable and resolved soon after supportive treatment. AEs associated with off-target activities such as atrial fibrillation, diarrhea, and major hemorrhage were not reported. Conclusions: Orelabrutinib-containing regimens demonstrated encouraging efficacy and well-tolerated safety profile among patients with MCD DLBCL. A large-scale prospective clinical study is on registration, which would offer a new potential therapeutic option for patients with MCD DLBCL.