Ferroptosis is a form of regulated cell death caused by iron-dependent lipid peroxidation. The glutathione-dependent lipid hydroperoxidase GPX4 prevents ferroptosis by converting lipid hydroperoxides into non-toxic lipid alcohols. Ferroptosis has been implicated in various degenerative diseases and is being explored as a therapeutic strategy to kill cancer cells by inhibiting GPX4. However, cancer cells vary in their sensitivity to GPX4 inhibitors, suggesting other factors may influence resistance. This study identifies FSP1 (previously known as AIFM2) as a potent ferroptosis resistance factor that acts in parallel to the GPX4 pathway. FSP1 is a myristoylated oxidoreductase that reduces coenzyme Q10 (CoQ), generating a lipophilic radical-trapping antioxidant (RTA) that halts lipid peroxidation. FSP1 expression correlates with ferroptosis resistance across cancer cell lines and mediates resistance in lung cancer cells. FSP1 is localized to the plasma membrane and functions as an NADH-dependent CoQ oxidoreductase, reducing CoQ to an RTA that suppresses lipid peroxidation. FSP1 operates in a non-mitochondrial CoQ antioxidant system that acts in parallel to the GPX4 pathway. These findings define a new ferroptosis suppression pathway and suggest that pharmacological inhibition of FSP1 may enhance the effectiveness of ferroptosis-inducing chemotherapies in cancer. FSP1 is a biomarker of ferroptosis resistance in many cancers, and its expression is important in predicting the efficacy of ferroptosis-inducing drugs. The study also highlights the potential of FSP1 inhibitors as a strategy to overcome ferroptosis resistance.Ferroptosis is a form of regulated cell death caused by iron-dependent lipid peroxidation. The glutathione-dependent lipid hydroperoxidase GPX4 prevents ferroptosis by converting lipid hydroperoxides into non-toxic lipid alcohols. Ferroptosis has been implicated in various degenerative diseases and is being explored as a therapeutic strategy to kill cancer cells by inhibiting GPX4. However, cancer cells vary in their sensitivity to GPX4 inhibitors, suggesting other factors may influence resistance. This study identifies FSP1 (previously known as AIFM2) as a potent ferroptosis resistance factor that acts in parallel to the GPX4 pathway. FSP1 is a myristoylated oxidoreductase that reduces coenzyme Q10 (CoQ), generating a lipophilic radical-trapping antioxidant (RTA) that halts lipid peroxidation. FSP1 expression correlates with ferroptosis resistance across cancer cell lines and mediates resistance in lung cancer cells. FSP1 is localized to the plasma membrane and functions as an NADH-dependent CoQ oxidoreductase, reducing CoQ to an RTA that suppresses lipid peroxidation. FSP1 operates in a non-mitochondrial CoQ antioxidant system that acts in parallel to the GPX4 pathway. These findings define a new ferroptosis suppression pathway and suggest that pharmacological inhibition of FSP1 may enhance the effectiveness of ferroptosis-inducing chemotherapies in cancer. FSP1 is a biomarker of ferroptosis resistance in many cancers, and its expression is important in predicting the efficacy of ferroptosis-inducing drugs. The study also highlights the potential of FSP1 inhibitors as a strategy to overcome ferroptosis resistance.