Peptides derived from mutated ras are immunogenic in mice and humans, and represent a group of specific tumor antigens that are potential targets for immunotherapy. T-cell responses against mutant p21 ras can be initiated in vitro by repeated stimulation of peripheral-blood mononuclear cells with mutant ras-derived peptides. Patients with tumors commonly harbouring ras mutations may therefore show evidence of in vivo reactivity against such mutations. Peripheral-blood mononuclear cells from 10 patients with colorectal adenocarcinoma were screened for reactivity against synthetic ras-derived peptides corresponding to the most commonly found mutations in this type of cancer. In one patient, T-cell reactivity against the 1–25, 13Gly [RIGHTWARDS ARROW] Asp peptide was detected. From this patient, both CD4+ and CD8+ T-cell clones specific for the 1–25, 13Gly [RIGHTWARDS ARROW] Asp mutation could be raised. We were not, however, able to detect the corresponding mutation in the cancer. The 13Gly [RIGHTWARDS ARROW] Asp mutation in the ras oncogene is frequent and constitutes 9 to 27% of all K ras mutations found in biopsies from patients with colorectal carcinomas. Our study demonstrates a mutant ras-specific T-cell response of both the CD4+ and the CD8+ phenotype in a cancer patient. We speculate that in this patient a specific T-cell response resulted in eradication of tumor cells harboring the 13Gly [RIGHTWARDS ARROW] Asp mutation. © 1994 Wiley-Liss, Inc.