Patients successfully treated for a malignancy with cytotoxic therapy have an increased risk of developing secondary myelodysplasia (MDS) and acute myeloid leukemia (AML). We report a patient in remission from Hodgkin's disease (HD) who remains hematologically normal 4 years after combination chemotherapy, but who has biological and genetic abnormalities characteristic of myelodysplasia. X-inactivation analysis using a 5' phosphoglycerate kinase (PGK) probe demonstrates polyclonal hematopoiesis, but cytogenetic analysis reveals a clonal population with a minority of metaphases having a 7q-deletion. NRAS mutations are not detectable 1 year after treatment, but are present in two separate clones (at codons 12 and 15) analyzed by single-stranded conformational polymorphism (SSCP), followed by cloning and sequencing 4 years after treatment. The presence of an activated NRAS with the same codon 12 mutation was independently confirmed by the nude mouse tumorigenicity assay. In vitro peripheral blood granulocyte-macrophage colony-forming units (CFU-GM) have changed from normal to undetectable levels while erythroid burst forming units (BFU-E) were significantly reduced on two occasions during the period of observation. These abnormalities are characteristic of MDS. Continued clinical follow-up will determine whether these evolving genetic and biological abnormalities pre-date the onset of clinical and morphological features of MDS.