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CD20 testing shortly after CD20-directed therapy can be difficult to interpret. We report an 89-year-old woman with multiply relapsed B-cell lymphoma who underwent excisional biopsy of an enlarging right axillary lymph node 17 days after the last dose of mosunetuzumab. A prior lymph node biopsy showed follicular lymphoma grade 3A with preserved CD20 expression. The relapse specimen showed diffuse large B-cell lymphoma of the germinal center B-cell subtype. Immunohistochemistry using the CD20 clone L26 failed to detect CD20 expression, whereas PAX5 and CD79a remained positive. Flow cytometry showed undetectable CD20 with clone L27; the large-cell gate contained CD19-positive B cells and showed kappa light-chain restriction. No morphologic findings of a lineage switch were observed. IGH and IGK rearrangement analyses demonstrated identical monoclonal peaks in the specimens obtained at the follicular lymphoma stage and relapse, supporting clonal continuity. Positron emission tomography/computed tomography revealed a 40-mm right axillary lymph node with a maximum standardized uptake value of 26.7. Epcoritamab was started as the seventh-line treatment despite negativity on routine assays for CD20. During step-up dosing, grade 1 cytokine release syndrome resolved after one dose of tocilizumab. Computed tomography on day 22 revealed a reduction in the size of the right axillary lymph node from 40 to 20 mm. The lesion remained 20 mm on days 41 and 51, with decreases in lactate dehydrogenase and soluble interleukin-2 receptor. Disease progression was documented on day 83. These findings suggest that negative CD20 results by routine assays shortly after mosunetuzumab therapy do not necessarily reflect true target loss. Integrated interpretation of histopathology, flow cytometry, and clonality studies may help guide subsequent CD20-directed treatment decisions.