Promising results have suggested human leukocyte antigen (HLA) class II as potential target for antibody-based lymphoma therapy. Thus, antibodies against HLA class II induced apoptosis in vitro, as well as complement-dependent cytotoxicity (CDC) and effector cell-mediated cytotoxicity (ADCC). Furthermore, animal models demonstrated strong antitumor effects in vivo. Importantly, early clinical studies with antibodies Lym-1 or Hu1D10, both against HLA-DR variants, suggested therapeutic potential. However, the increased risk of serious toxicity may require an improved understanding of the clinically relevant mechanisms of action of HLA class II-directed antibodies, which may then allow generation of optimized antibody constructs to achieve optimal therapeutic efficacy.