Human histocompatibility antigens HLA-A, HLA-B, and HLA-C are a complex of two noncovalently associated subunits: a heavy chain glycoprotein (alpha) carrying the genetic polymorphism and an invariant light chain, beta 2-microglobulin (beta 2m). Upon incubation of papain-solubilized HLA with radiolabeled urinary beta 2m, the latter is incorporated into HLA, where it substitutes for the preexisting beta 2m that has dissociated from the complex. The association-dissociation equilibrium that governs this beta 2m exchange reaction was investigated and found to be characterized by a long lifetime of the complex (half-life of 80 min at 37 degrees C) and a relatively low Kd (4 nM). The beta 2m exchange was used as the basis of a radioimmunoassay for HLA antigens with radiolabeled beta 2m as a unique label for all HLA specificities. In a similar fashion, radiolabeled beta 2m can be incorporated into HLA at the cell surface. Although the process is slower and less extensive than in solution, it can be used as a means to tag cells with specific probes for HLA antigens.