Cytochrome b5 domain containing 2 (CYB5D2) (neuferricin) belongs to the family of membrane-associated progesterone receptors (MAPRs). MAPRs affect multiple cellular processes, including proliferation, differentiation, and survival. Consistent with these observations, we report here that CYB5D2 enhances HeLa cells survival of etoposide (ETOP)-mediated cytotoxicity. Overexpression of CYB5D2 enhanced the survival of HeLa cells compared with HeLa cells transfected with empty vector (EV) upon ETOP treatment. As ETOP initiates ATM-dependent DNA damage response (DDR), we were able to show that CYB5D2 did not affect ETOP-induced DDR. In line with these observations, CYB5D2 did not protect HeLa cells from UV-induced cytotoxicity. Additionally, CYB5D2 had no effects on TNFα-induced apoptosis. Collectively, CYB5D2 enhances HeLa cell survival of ETOP-induced cytotoxicity with some specificity. CYB5D2 contains a cytochrome b5 (cyt-b5) domain and a transmembrane (TM) motif. Both domains are required for CYB5D2-mediated protection of HeLa cells from ETOP-induced cytotoxicity. In an effort to search for the underlying mechanisms, we have profiled gene expression between HeLa–CYB5D2 and HeLa–EV cells. Although ectopic CYB5D2 does not massively alter gene expression, the expression of several transcripts was affected more than 2-fold, suggesting that they may contribute to CYB5D2-mediated HeLa cell survival of ETOP treatment.