Rituximab is the first line drug to treat non Hodgkin's lymphoma (B-NHL) alone or in combination with chemotherapy. However, 30-40% of B-NHL patients are unresponsive to rituximab or resistant after therapy. Human phosphatidylethanolamine-binding protein 4 (hPEBP4) is a novel member of PEBP family and functions as an anti-apoptotic molecule. In this study, we found hPEBP4 to be expressed in up to 90% of B-cell lymphoma patients, but in only 16.7% of normal lymph nodes. Interestingly, hPEBP4 overexpression inhibited rituximab-mediated complement dependent cytotoxicity (R-CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) in B-NHL cells while downregulation of hPEBP4 augmented the therapeutic efficacy of rituximab both in vitro and in vivo. Furthermore, hPEBP4 silencing sensitized the primary B-acute lymphocytic leukemia (B-ALL) cells to R-CDC. During rituximab-mediated complement dependent cytotoxicity, hPEBP4 was recruited to the cell membrane in a PE-binding domain dependent manner and inhibited R-CDC induced calcium flux and reactive oxygen species (ROS) generation. These events contributed to the decrease of cell death induced by R-CDC in B-cell lymphomas. Meanwhile, hPEBP4 knockdown potentiated the chemosensitization of the rituximab in B-cell lymphoma cells by regulating the expression of Bcl-xl, Cycline E, p21(waf/cip1) and p53 and the activation of caspase-3 and caspase-9. Considering that hPEBP4 conferred cellular resistance to rituximab treatment and was preferentially expressed in lymphoma tissue, it could be a potential valuable target for adjuvant therapy for B-cell lymphoma.