Ofatumumab is a type I fully human monoclonal antibody (IgG1) that binds to a unique epitope on the human CD20 molecule expressed on the surface of B cells. It binds specifically to both the small and large extracellular loops of the CD20 molecule. A phase I-II study demonstrated that ofatumumab was well tolerated and resulted in objective responses. In a phase II study of ofatumumab in fludarabine- and alemtuzumab-refractory chronic lymphocytic leukemia (CLL) or fludarabine-refractory CLL with bulky (> 5 cm) lymphadenopathy, the response rates were 58% and 47%, respectively. This study led to accelerated approval of ofatumumab by the U.S. Food and Drug Administration for the treatment of CLL refractory to fludarabine and alemtuzumab. In a phase II study of ofatumumab with fludarabine and cyclophosphamide in untreated CLL, patients were randomized to ofatumumab 500 mg (group A) or 1000 mg (group B) (initial dose, 300 mg, both groups), combined with fludarabine and cyclophosphamide. The higher ofatumumab dose resulted in a higher complete response (CR) rate (50%), compared to the lower-dose ofatumumab group (CR, 32%) (overall response rates, 77% and 73%, respectively). A phase III study of ofatumumab combined with fludarabine and cyclophosphamide versus fludarabine and cyclophosphamide in relapsed CLL are ongoing, as well as several clinical trials of ofatumumab. Ofatumumab has significant antileukemic activity and ongoing clinical trials will determine the role of ofatumumab in CLL.