Background Gene expression profiling has successfully identified the prognostic significance of the host response in lymphomas. The aggressive T cell/histiocyte rich large B cell lymphoma (THRLBCL) and the indolent nodular lymphocyte predominant Hodgkin's lymphoma (NLPHL) are both characterized by a paucity of tumor cells embedded in an overwhelming background. The tumor cells of both lymphomas share several characteristics, while the cellular composition of their microenvironment is clearly different. DESIGN AND METHODS: We collected 33 THRLBCL and 56 NLPHL cases and performed microarray gene expression profiling on 10 cases of each lymphoma, to obtain a better understanding of the lymphoma host response. By quantitative RT-PCR we verified that these 20 selected cases were representative for the entire THRLBCL and NLPHL population. RESULTS: We observed that the NLPHL microenvironment is molecularly very similar to a lymph node characterized by follicular hyperplasia, while the THRLBCL microenvironment is clearly different. The THRLBCL signature is hallmarked by up-regulation of CCL8, IFN-g, IDO, VSIG4 and Toll-like receptors. These features may be responsible for the recruitment and activation of T cells, macrophages and dendritic cells, characterizing the stromal component of this lymphoma, and may point towards innate immunity and a tumor tolerogenic immune response in THRLBCL. Conclusions The gene expression profile of THRLBCL, in comparison with that of NLPHL, shows features suggestive of a distinct tolerogenic host immune response that may play a key role in the aggressive behavior of this lymphoma, and that may serve as a potential target for future therapy.