Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare skin-tropic hematological malignancy of uncertain pathogenesis and poor prognosis. We examined 118 BPDCN cases for cytomorphology, MYC locus rearrangement, and MYC expression. Sixty-two (53%) and 41 (35%) cases showed the classic and immunoblastoid cytomorphology, respectively. Forty-one (38%) MYC⁺BPDCN (positive for rearrangement and expression) and 59 (54%) MYC⁻BPDCN (both negative) cases were identified. Immunoblastoid cytomorphology was significantly associated with MYC⁺BPDCN. All examined MYC⁺BPDCNs were negative for MYB/MYBL1 rearrangement (0/36). Clinically, MYC⁺BPDCN showed older onset, poorer outcome, and localized skin tumors more commonly than MYC⁻BPDCN. MYC was demonstrated by expression profiling as one of the clearest discriminators between CAL-1 (MYC⁺BPDCN) and PMDC05 (MYC⁻BPDCN) cell lines, and its shRNA knockdown suppressed CAL-1 viability. Inhibitors for bromodomain and extra-terminal protein (BETis), and aurora kinases (AKis) inhibited CAL-1 growth more effectively than PMDC05. We further showed that a BCL2 inhibitor was effective in both CAL-1 and PMDC05, indicating that this inhibitor can be used to treat MYC⁻BPDCN, to which BETis and AKis are probably less effective. Our data will provide a rationale for the development of new treatment strategies for patients with BPDCN, in accordance with precision medicine.