A twin pair affected by juvenile myelomonocytic leukemia (JMML) with the same somatic PTPN11 mutation and abnormal chromosome 7 in bone marrow samples but distinct prognostic gene expression signatures, received a matched-unrelated donor and matched-unrelated cord blood transplant, respectively. Both twins fully engrafted, but after 6 months, the twin with an acute-myeloid-like (AML-like) signature at diagnosis rejected the graft and had an autologous reconstitution. A second transplant with an unrelated 5/6-HLA-matched-loci cord blood performed after 4 months from rejection was unsuccessful. After 25 months from diagnosis, the twin with the AML-like gene expression signature died of liver failure while on progression of his JMML. The other twin, who had a non-acute-myeloid-like (non-AML-like) gene expression signature at diagnosis is in complete hematological remission with full donor chimera. This observation suggests a biological diversity of JMML also in patients with a common genetic background.