Interleukin-12 (IL-12) is a cytokine that facilitates cytolytic T-cell responses, enhances the lytic activity of NK cells and induces the secretion of interferon-gamma by both T and NK cells. Binding of rituximab, a chimeric murine/human monoclonal antibody, to CD20 on B-lymphocytes induces apoptosis and the Fc domain of the antibody recruits immune effector functions to mediate cell lysis. Therefore, combining IL-12 with rituximab in patients with B-cell non-Hodgkin lymphoma (NHL) may augment the immune mediated cell lysis induced by rituximab. To determine whether a synergistic effect exists when IL-12 is given in combination with rituximab, clinical trials are being done to evaluate the clinical efficacy of the combination. The two agents, when given in combination, significantly upregulate the patient's immune mechanisms. The combination upregulates gamma interferon and IP-10 expression and increases NK cell lytic activity. The combination appears to have significant clinical activity with a high clinical response rate in early phase clinical trials. However, a randomized controlled trial will be required to determine whether the addition of IL-12 adds to the efficacy of rituximab in B-cell NHL.