ARTICLE ABSTRACTFollicular lymphoma commonly recurs and is difficult to cure. Obinutuzumab is a humanized glycoengineered type II anti-CD20 antibody with a mode of action that includes induction of antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and direct cell death. There is no evidence on the effectiveness of retreatment with obinutuzumab in patients with prior obinutuzumab treatment. Using obinutuzumab-induced direct-cell-death–resistant cells, we investigated the efficacy of obinutuzumab retreatment in combination with chemotherapeutic agents used in follicular lymphoma treatment. Human non-Hodgkin lymphoma SU-DHL-4 cells were sustainably exposed to obinutuzumab in vitro, and 17 resistant clones expressing CD20 and showing 100-fold higher IC50 of obinutuzumab than parental cells were established. The growth inhibition effect of obinutuzumab in combination with bendamustine, 4-hydroperoxy-cyclophosphamide, doxorubicin, vincristine, or prednisolone was estimated using an interaction index based on the Bliss independence model. For each clone, there were various combinations of obinutuzumab and chemotherapeutic agents that showed supra-additive effects. Obinutuzumab combined with doxorubicin enhanced caspase-dependent apoptosis and growth inhibition effect. Obinutuzumab combined with prednisolone enhanced DNA fragmentation and G0–G1 arrest. These combinations also had an antitumor effect in mouse xenograft models. Our results indicate that retreatment with obinutuzumab, when it is combined with chemotherapeutic agents, is effective in the CD20-positive obinutuzumab-induced direct-cell-death–resistant cells.