Peptide epitopes for tumor‐reactive cytotoxic T‐lymphocytes (CTL) have been identified on human cancers and are being used in tumor vaccine trials. However, the pharmacokinetics and pharmacodynamics of such peptides have been inadequately studied. It is predicted that immunogenic tumor peptides would have short half‐lives in vivo. The goal of the present work was to evaluate the stability of the immunogenic peptide MART‐1_27–35 in fresh normal human plasma (NHP) and to identify modifications that convey protection against enzymatic destruction without loss of immunogenicity. We evaluated the stability of the MART‐1_27–35 peptide (AAGIGILTV) and modified forms of that peptide for stability and immune recognition in an in vitro model. The peptides were incubated in plasma for varied time intervals and evaluated for their ability to reconstitute the epitope for MART‐1_27–35‐reactive CTL. Loss of CTL reactivity signaled loss of immunoreactive peptide. When 1 μM MART‐1_27–35 peptide was incubated in plasma prior to pulsing on target cells, CTL reactivity was lost within 3 hr, and the calculated half‐life of this peptide was 22 sec. This degradation was mediated by peptidases. The stability of MART‐1_27–35 was markedly prolonged by C‐terminal amidation and/or N‐terminal acetylation (peptide capping), or by polyethylene‐glycol modification (PEGylation) of the C‐terminus. These modified peptides were recognized by CTL. The MART‐1_27–35 peptide is very unstable in plasma. It is probable that it and other immunogenic peptides will be similarly unstable in vivo. Immunogenicity of these peptides might be enhanced by creating modifications that enhance stability. Int. J. Cancer 83: 326–334, 1999. © 1999 Wiley‐Liss, Inc.