The availability of safe and effective monoclonal antibodies (mAbs) has dramatically altered treatment strategies for B-cell malignancies. Rituximab, a type I chimeric anti-CD20 mAb, not only has activity against a broad range of CD20-positive B-cell malignancies but also, when combined with chemotherapy or other biologic agents, has improved response rates; in addition, in certain situations, progression-free survival and even overall survival may be prolonged. Recently, other anti-CD20 mAbs have been developed to improve on the activity achieved with rituximab or to demonstrate efficacy in patients whose diseases are resistant to rituximab. The most extensively studied of these is ofatumumab, a type I human antibody that binds to a different epitope of CD20 than rituximab. Preclinical data suggest improved complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity compared with rituximab. In early clinical trials, ofatumumab demonstrated single-agent activity against chronic lymphocytic leukemia (CLL) and a number of histologies of B-cell non-Hodgkin's lymphomas. This antibody was recently approved by the US Food and Drug Administration for the treatment of CLL that is resistant to both fludarabine and alemtuzumab. Additional study is ongoing with ofatumumab in combination with chemotherapy and biologic agents to further enhance its efficacy. Ofatumumab offers another effective agent with which to improve the outcome of patients with B-cell malignancies.