Spontaneous regression of widespread lesions is a characteristic feature of neuroblastoma. One may postulate that the immune response contributes to these clinical regressions. Accordingly, we studied the T-cell receptor (TCR) repertoire of tumor-infiltrating lymphocytes in eight neuroblastoma tumors. The expression of 29 Vα and 24 Vβ gene segment subfamily specificities was analyzed by PCR and compared by computerized densitometry of Southern blots to values obtained in the blood. Overall, the TCR repertoire of these eight patients was diverse, with virtually all Vα and Vβ specificities expressed. Nonetheless, four of these patients showed Vβ2 gene segment subfamily overexpression in the tumor corresponding to local expansion of polyclonal T-cell subpopulations. In one patient, this expansion could be due to local secretion of superantigenic activity, as suggested by the specific stimulation of murine T cells expressing a human Vβ2 chain by supernatant of the corresponding neuroblastoma cell line. In addition, high-resolution analysis of the TCR β transcript complementarity-determining region 3 sizes identified three patients (of six studied) with marked clonal T-cell expansion in the tumor not seen in the blood. The specific expression of several dominant clonotypes in the tumor may be related to the recognition of neuroblastoma-specific antigens in these patients. Together, these results on the TCR repertoire expressed in vivo may lead to the characterization of putative immune response mechanisms (i.e., antigen- or superantigen-driven stimulation) which participate in tumor regression.