TAPA-1 is a transmembrane protein that has been shown to be involved in cell growth and cellular adhesion. Our studies were aimed at determining the mechanisms of the biologic phenomena mediated by TAPA-1, which include the identification of proteins that are associated with it on the surface of lymphocytes. We and others have previously shown that Leu-13, a leukocyte Ag, is one such molecule and that in B cells TAPA-1 is associated with the CD19 Ag. Herein we identify an additional molecule, HLA-DR, that is noncovalently associated on the surface of B cells with TAPA-1. This association was first detected by immunoprecipitation by anti-TAPA-1 and by anti-HLA-DR antibodies in the presence of mild detergents. The initial observation was confirmed by 2-dimensional SDS-PAGE and by direct identification of TAPA-1 in anti-HLA-DR immunoprecipitates by Western blot analysis. The association of the two molecules on the surface of a human B cell line was shown by cocapping experiments. In addition, antibodies to both molecules can induce cellular adhesion and an antiproliferative effect. Because the tissue distribution of these two molecules only partially overlaps, with TAPA-1 being expressed on most cell types and MHC class II expressed on a more restricted group of tissue, it is possible that the TAPA-1 molecule provides a basic function that can augment a cell type specific activity. In B cells the association of TAPA-1 with CD19 and HLA-DR may increase cellular interaction and play a supporting role in the transmission of specific signals.