The interaction between Heligmosomoides polygyrus superantigen and human peripheral blood mononuclear cells (PBMC) was evaluated. Parasite homogenate and excretory–secretory proteins from both L4 larvae and adult worms were examined for their ability to stimulate, and be presented by, human cells. Proliferation assays using PBMC from 3 human volunteers indicated that naïve cells were stimulated by H. polygyrus superantigen. Antigen presenting cells (APC) from a number of human donors were able to successfully present H. polygyrus superantigen to mouse T cell hybridomas. However, this ability varied according to the source of the superantigen, and human APC, in contrast to APC from mice, could only present the superantigen contained within parasite homogenate. Also, in contrast to the situation with mice, human APC could present H. polygyrus superantigen to stimulate mouse T cells expressing not only TCR Vβ8.1, but also TCR Vβ7. Therefore, H. polygyrus superantigen can successfully stimulate, and be presented by, human PBMC of different MHC haplotypes, although the cellular mechanisms appear to be different from those observed in the mouse.