Epcoritamab, a subcutaneous CD3xCD20 bispecific antibody approved for relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma, is being evaluated in regimens containing CD20-targeted monoclonal antibodies (e.g. rituximab plus cylophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP]). To demonstrate combinability of epcoritamab with CD20 monoclonal antibodies (mAbs), potential interference of rituximab or obinutuzumab with epcoritamab was investigated. While there was dose-dependent binding interference between CD20 mAbs and epcoritamab through steric hindrance, ex vivo assays using tumor cell lines, R-CHOP-treated patient samples, and an animal model showed this did not impair tumor cell killing. In a pharmacokinetic model, >90% maximal cytotoxicity was predicted after the first full epcoritamab dose in the presence of therapeutic rituximab concentrations due to effective tumor-epcoritamab-T-cell trimer formation. Immunoprofiling of R-CHOP-treated DLBCL patient samples showed emergence of less-differentiated CD8 memory T cells, further supporting the feasibility of the combination in ongoing studies of epcoritamab with rituximab-containing chemoimmunotherapy.