The frequency of N- and K-ras oncogene mutations was investigated in plasma cell dyscrasias. Genomic DNAs from 128 patients were selected for this study: 30 monoclonal gammopathies of undetermined significance, 8 solitary plasmacytomas, 77 multiple myelomas (MM), and 13 plasma cell leukemias (PCL). A two-step experimental approach was devised. All samples were screened for mutations by single-strand conformation polymorphism analysis. DNA fragments displaying an altered electrophoretic mobility were further studied by direct sequencing to confirm and characterize the nature of the mutations. Ras mutations are not randomly distributed because they are detectable only in MM (9%) and PCL (30.7%). N-ras codons 12, 13, and 61 and K-ras codon 12 were found to be mutated, but N-ras codon 61 mutation was the most frequent finding (63.6%). In conclusion, ras mutations were found in PCL, and in a subset of MM characterized by advanced-stage disease and adverse prognostic parameters. Furthermore, based on our findings, it is possible to speculate that ras mutations represent a late molecular lesion in the process of multistep carcinogenesis.