The aim of this study was to develop a new class of antibody-drug conjugates (ADCs) with the potential to not only enhance treatment efficacy but also improve tolerability for patients with B-cell lymphomas. Classic ADCs consist of monoclonal antibodies (mAbs) linked to drugs or toxins. They selectively deliver toxic moieties to tumor cells. As such, they greatly improve the therapeutic index compared to traditional chemotherapeutic agents. However, the therapeutic efficacy and safety of ADCs are dependent on linker stability and payload toxicity. Limited payload number on a single antibody (drug-to-antibody ratio, or DAR) has been driving investigators to use extremely toxic agents; however, even very low off-target binding of these ADCs may kill patients. Herein we report a new design of ADCs that consists of rituximab (RTX) and N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer–epirubicin conjugates. The latter was selectively attached to RTX via reduced disulfide bonds. Such design allows the introduction of a large payload of drug on the antibody without adding attachment sites and without compromising the antigen-targeting ability. The binding of the new conjugate, namely RTX-P-EPI, to Ramos cells (with high CD20 expression) was confirmed. The cytotoxicity of RTX-P-EPI against Raji and Ramos cells was also determined. Interestingly, two-fold inhibition of cell proliferation was observed when using RTX-P-EPI compared with their equivalent physical mixture of RTX and P-EPI. Treatment of male SCID mice bearing subcutaneous Ramos B-cell lymphoma tumors demonstrated that RTX-P-EPI possessed superior efficacy when compared to combination of RTX with chemotherapy EPI (RTX + EPI) and P-EPI (RTX + P-EPI), whereas single RTX and a non-specific conjugate IgG-P-EPI only showed marginal effect. The conjugate RTX-EPI in which EPI was directly attached to RTX demonstrated much less antitumor activity compared with RTX-P-EPI. The results suggest that this new design possesses synergistic potential of immunotherapy combined with established macromolecular therapy; moreover, a conventional chemo-agent could be utilized to generate highly effective ADCs and to achieve lower risk of off-target toxicity.