Several investigators have reported an association between insulin-dependent diabetes mellitus (IDDM) and an RFLP detected with a probe for the constant region of the beta chain (C beta) of the human T-cell receptor (TCR). A likely hypothesis is that the closely linked TCR variable (V beta) region genes contribute to IDDM susceptibility and that the association with the TCR C beta locus reflects this contribution, via linkage disequilibrium between V beta and C beta. The products of the beta-chain genes might be expected to be involved in the etiology of IDDM because of the autoimmune aspects of IDDM, the known involvement of HLA, and the necessity for TCR and HLA molecules to interact in an immune response. In order to investigate the hypothesis, we tested for linkage between IDDM and V genes encoded at either the TCR beta locus on chromosome 7 or the TCR alpha locus on chromosome 14, using 36 families with multiple affected sibs. No excess sharing of haplotypes defined by V alpha or V beta gene RFLPs was observed in affected sib pairs from IDDM families. We also studied unrelated IDDM patients (N = 73) and controls (N = 45) with the C beta RFLP but were unable to confirm the reported association even when the sample was stratified by HLA-DR type. Our results are incompatible with close linkage, in the majority of families, between either the TCR alpha or TCR beta locus and a gene making a major contribution to susceptibility to IDDM.