B-cell lymphoma-extra large (Bcl-XL) has been known to suppress serum deprivation-induced cell death, while reactive oxygen species modulator 1 (Romo1) is responsible for a serum deprivation-induced increase in reactive oxygen species (ROS). Therefore, we investigated whether Bcl-XL expression could inhibit the serum deprivation-induced increase in ROS and cell death, which are mediated by Romo1. We found that Bcl-XL expression effectively blocked serum deprivation- and Romo1-triggered ROS generation. Bcl-XL also inhibited apoptotic cell death induced by both serum deprivation and oxidative stress. From these results, we suggest that increased Bcl-XL expression, which is observed in many cancer cells, confers resistance to oxidative stress in the cancer cells by suppressing Romo1-mediated oxidative stress.