Here, we demonstrate the possible involvement of oxidative stress in altered CD13/aminopeptidase N (APN) expression during myeloid cell differentiation induced by TPA. In flow cytometrical analysis, CD13/APN protein was constitutively expressed in HL-60 cells. When the cells were treated with TPA, CD13/APN expression was up-regulated with increased intracellular peroxides and a morphological change into macrophage-like cells. This increase in CD13/APN expression was suppressed by treatment with N-acetylcysteine. Transfection of Mn-superoxide dismutase (MnSOD) gene to the cells also suppressed the up-regulated CD13/APN expression. Furthermore, a neutralizing antibody to TNFalpha partially blocked this up-regulation. These results indicate that the change in intracellular redox state could be involved in the up-regulation of CD13/APN expression during TPA-induced differentiation of HL-60 cells, suggesting that TNFalpha may serve as, at least, one of the signals stimulated by TPA.