An 11-day-old boy presented with Down syndrome (DS) facies, pallor, irritability, tachypnea, pan-systolic murmur, and hepatosplenomegaly. Hemoglobin was 98 g/L, white cells were 254 × 109/L, and platelets were 31 × 109/L. Peripheral blood film displayed 95% blast cells having deeply basophilic cytoplasm with blebs, multiple nucleoli, and a few target cells. Circulating blasts were CD34+, CD36+, CD117+, CD13-, CD33-, and MPO-. Trisomy 21 was the sole cytogenetic abnormality. The parents refused treatment and the neonate died. TMD was the presumed diagnosis. TMD is seen in 10% of neonates with DS. Its clinical, morphologic, and phenotypic features are indistinguishable from acute megakaryocytic leukemia (AMKL) but the blasts universally show trisomy 21 in TMD. Spontaneous remissions occur often but fatal forms are seen in 16% to 23% of cases