Previous studies have shown p53 germ-line mutations in some familial cancer aggregations with or without the Li-Fraumeni syndrome (LFS). Such mutations were also reported in children and young adults with second malignant neoplasms (SMN). This led us to screen for p53 germ-line mutations in a group of seven patients affected with SMN, but characterized by an older age of onset than in the previous reports. No mutation was found in exons 4 to 8 and their boundaries using the single-strand conformation polymorphism technique. Our results give strong evidence for genetic heterogeneity of SMN, probably related to the age of cancer onset.