Induced pluripotent stem cells (iPSCs) have the potential to differentiate into any cell in the body and thus have attractive regenerative medicine potential. Current iPSC generation protocols, however, have low efficiency and show variable quality among clones. This variability influences the efficiency and reproducibility of iPSC differentiation. Our previous study reported that MYC proteins (c-MYC and MYCL) are important for the reprogramming efficiency and germline transmission of iPSCs, but that MYCL can generate iPSC colonies more efficiently than c-MYC. However, why c-MYC and MYCL cause different reprogramming efficiencies is unknown. In this study, we found that MYC Box 0 (MB0) and MB2, two functional domains conserved in the MYC protein family, contribute to the phenotypic difference and promote iPSC generation in MYCL-induced reprogramming. Proteome analysis suggested that in MYCL-induced reprogramming, cell adhesion-related cytoskeletal proteins are regulated by the MB0 domain, while RNA processes are regulated by the MB2 domain. These findings provide a molecular explanation for why MYCL has higher reprogramming efficiency than c-MYC.