Up to 15% of acute promyelocytic leukemia (APL) patients fail to achieve or maintain remission. We investigated a common G > A polymorphism at position -1377 (rs2234767) in the core promoter of the CD95 cell death receptor gene in 708 subjects with acute myeloid leukemia, including 231 patients with APL. Compared with the GG genotype, carrier status for the -1377A variant was associated with a significantly worse prognosis in APL patients. Carriers were more likely to fail remission induction (odds ratio = 4.22; 95% confidence interval, 1.41-12.6, P = .01), were more likely to die during the first 8 weeks of remission induction therapy (hazard ratio = 7.26; 95% confidence interval, 2.39-22.9, P = .0005), and had a significantly worse 5-year overall survival (odds ratio = 2.14; 95% confidence interval, 1.10-4.15, P = .03). The -1377A variant destroys a binding site for the SP1 transcriptional regulator and is associated with lower transcriptional activity of the CD95 promoter. Identifying patients at high risk of life-threatening events, such as remission induction failure, is a high priority in APL, especially because such events represent a major cause of death despite the introduction of differentiation therapy.