To elucidate the clinical and morphological differences between de novo acute myeloid leukemia (AML) with trilineage myelodysplasia (AML/TMDS) and AML developed from de novo myelodysplastic syndrome (MDS), we analyzed 12 and 13 cases, respectively. The median age of AML/TMDS patients was lower, but not significantly so, than the median age of patients with AML from MDS (45 vs 55 years). Platelet counts and the percentage of peripheral blasts were significantly higher in the patients with AML/TMDS than in the patients with AML from MDS (p < 0.05 and p < 0.01, respectively). Four patients with AML from MDS could not be classified into FAB subtypes. Eight patients (67%) with AML/TMDS achieved complete remission (CR). Nine with AML from MDS were treated with less intensive regimens; none of these patients achieved CR. In the comparison of dysplastic changes in both groups, the rate of pseudo-Pelger anomaly was significantly higher in the patients with AML from MDS (p < 0.001), and micromegakaryocytes and multinuclear erythroblasts were also more frequent in the patients with AML from MDS than in those with AML/TMDS (p < 0.05). The overall survival curves showed that the 12 patients with TMDS had a significantly better survival than the 13 patients with AML from MDS (p < 0.01). Our findings suggest that AML/TMDS is a subtype of de novo AML and is different from AML from MDS. Further study is required to determine the biological differences between AML with TMDS and AML transformed from MDS.