Many CTL epitopes of clinical importance, particularly those derived from tumor Ags, display relatively poor MHC binding affinity and stability. Because in vivo immunogenicity, and thus the efficacy of peptide-based vaccines, is thought to be determined by MHC/peptide complex stability, there is a need to develop a simple strategy for enhancing the binding of suboptimal epitopes. Toward this goal, the ability to enhance suboptimal peptides through covalent linkage to β 2-microglobulin (β 2 m) was explored. Two suboptimal variants of a high-affinity D b-restricted influenza nucleoprotein peptide were covalently linked, via a polypeptide spacer, to the amino terminus of human β 2 m and the recombinant fusion proteins expressed in Escherichia coli. When compared with their uncoupled counterparts, the β 2 m-linked epitopes display enhanced MHC stabilization and antigenicity. Thus, tethering epitopes to β 2 m provides a simple method for augmenting the biological activity of suboptimal peptides and could be useful in the design of peptide-based vaccines or immunotherapeutics.