FLT3 gene internal tandem duplication (ITD) and activating loop mutations (D835) were determined in 22 cases of therapy-related acute myelocytic leukemia/myelodysplastic syndrome (t-AML/MDS) and 102 cases of de novo AML/MDS. In t-AML/MDS, FLT3 ITD was absent, and D835 was found in only one case of therapy-related acute promyelocytic leukemia (APL). In de novo AML/MDS, however, FLT3 ITD and D835 were significantly more frequent (28 of 102 cases, P=0.024) and were associated with high peripheral blood and marrow blast counts. Our results suggest that different pathogenetic pathways might be involved in t-AML/MDS and de novo AML/MDS.