Most non-Hodgkin B-cell lymphomas (NHLs) are characterized by the clonal expansion of a single cell expressing a unique rearranged immunoglobulin gene. This idiotype (Id) is a tumor-specific antigen that can be immunologically targeted. The therapeutic efficacy of Id-based vaccines correlates best with detection of cellular immune responses, although these have not been as well characterized as the humoral responses. This study exploited a molecular approach to modify the Id of 38C13 lymphoma for processing via class I and II antigen-processing pathways and evaluated protein expression in dendritic cells (DCs) to simultaneously stimulate tumor reactive CD8(+) and CD4(+) lymphocytes. Recombinant vaccinia viruses (rVVs) were constructed, coding for Id fused with the targeting signal of the lysosomal-associated membrane protein1 (Id-LAMP1) to promote antigen presentation in the context of major histocompatibility complex (MHC) class II. Mature DCs infected with rVV/Id-LAMP1 elicited both CD4(+) and CD8(+) Id-specific T cells and protected animals from tumor challenge. Id-specific CD8(+) cells were required to mediate the effector phase of a therapeutic response, and CD4(+) cells were beneficial in the induction phase of the response. These results demonstrate that fusing Id to LAMP1 enhances CD8(+) and CD4(+) Id-specific responses for NHLs and may be useful therapeutically.