Thalidomide and lenalidomide are immunomodulatory drugs that show promise in mantle cell lymphoma (MCL). In this study, their potential mechanisms of action against MCL cells were investigated, both alone and in combination with rituximab. Thalidomide, lenalidomide and rituximab have no direct effect on MCL cell viability. However, both immunomodulatory drugs indirectly affect viability by enhancing peripheral blood mononuclear cell-mediated cytotoxicity, with lenalidomide inducing significantly higher levels of toxicity than thalidomide. Rituximab induces both complement-dependent and antibody-dependent cellular cytotoxicity (ADCC) against MCL cells. Rituximab-induced ADCC is enhanced by lenalidomide and, to a lesser extent, thalidomide. Preliminary in vivo findings in MCL patients treated with thalidomide support a role for natural killer cells in the efficacy of these drugs. In conclusion, our data support a role for immunomodulatory drugs in the treatment of MCL.