Prior to the binding of antigenic peptide, a complex of chaperone proteins associates with the Major Histocompatibility Complex (MHC) class I heavy chain/beta2m heterodimer. Although each domain of the MHC class I heavy chain contains amino acid residues that influence chaperone binding, there are several pieces of evidence that point to an interaction between the MHC class I alpha/2/alpha3 domains and tapasin. In regard to the site on tapasin involved in the tapasin/MHC interface, we have found that a particular region of tapasin (containing amino acid residues 334-342) is necessary for the binding of tapasin to the MHC class I heavy chain. Our results also indicate that amino acids in this region of tapasin also affect the proportion of MHC class I open forms expressed at the cell surface and MHC class I egress from the endoplasmic reticulum. Based on these results and those obtained by other laboratories, a model for MHC class I/tapasin interaction is proposed.