Glycolytic cancers are resistant to many forms of chemotherapy and some respond poorly to differentiation therapies. Here, we investigate the effects of exposure to all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) on differentiation and cell survival in the human leukemia cell line, HL60 and its mitochondrial gene knockout mutant, HL60rho0. Glycolytic HL60rho0 cells exposed to single and combined treatments expressed less CD15, in most cases, but produced a stronger respiratory burst than parental HL60 cells. HL60rho0 cells were also significantly more resistant to apoptosis after combined ATO+ATRA treatment compared with HL60 cells, and this was associated with failure to upregulate Fas expression.