Tumor necrosis factor (TNF) related apoptosis inducing ligand (TRAIL) can induce the apoptosis of tumor cells, but leaving its effect on malignant lymphoma largely insignificant, as these tumors may develop drug resistance. Chlorambucil (CLB) had definitive treatment efficacy on low-malignant non-Hodgkin lymphoma (NHL), but with unclear efficacy on highly malignant Burkitt lymphoma. A study has been shown that CLB could enhance the sensitivity of chronic lymphatic leukemia cells against TRAIL. This work aims to investigate the effect of CLB combined with TRAIL on in vitro proliferation and apoptosis of Raji cells. TRAIL (0, 20, 40 and 80 ng/ml) or CLB (0, 2.5 5 and 10 μM) was used to treat Raji cells. Cell counting kit 8 (CCK-8) was used to test proliferation whilst flow cytometry was employed to examine the apoptosis. The effect of TRAIL or CLB treatment on expression of death receptor 4 (DR4) and DR5 was tested. Combined treatment (80 ng/ml TRAIL and 10 μM CLB) was adopted for observing Raji cell proliferation and apoptosis. Single treatment of TRAIL or CLB has weak effects of inducing apoptosis or inhibiting proliferation. TRAIL concentration has no significant effects on DR4/DR5 expression in Raji cells, whilst CLB treatment elevated those gene expressions. Combined treatment of TRAIL and CLB had more potent effects regarding cell proliferation inhibition or apoptosis induction compared to single treatment. TRAIL or CLB has weak inhibitor effects on Raji cell proliferation or induction of apoptosis. Via up-regulating DR4 and DR5 expression, CLB has synergistic effects with TRAIL to potentiate the apoptotic induction and proliferation inhibition role.