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Objective In humans, haptoglobin (Hp) exists in two allelic forms, Hp1 and Hp2, that differ significantly in their ability to protect the organism from oxidative stress. It has been proposed that in patients with diabetes mellitus carriers of the Hp2-2 genotype may benefit from vitamin E supplementation. Aim of our study was to investigate if there is evidence regarding a potential interaction between the Hp polymorphism and vitamin E with regard to mortality in individuals at medium-to-high cardiovascular risk with and without diabetes mellitus.Research design and methods Data from 3176 participants of the Ludwigshafen Risk and Cardiovascular Health study, a monocentric hospital-based study of patients referred for coronary angiography, were analysed using Cox proportional hazard regression.Results Participants with the Hp2-2 genotype demonstrated significantly lower Hp levels, while carriers of at least one Hp-2 allele displayed elevated levels of the inflammatory markers high-sensitive C reactive protein and serum amyloid A. No notable differences in comorbidities were observed among the various HP genotype groups. While the HP genotype showed no direct association with mortality, a borderline significant correlation between α-tocopherol plasma concentration and overall mortality was noted. An interaction between vitamin E status and the HP genotype regarding mortality risk was evident, particularly among patients with diabetes mellitus, with a p value of 0.021 for the interaction term. In restricted cubic splice analysis, patients with diabetes mellitus who are carriers of the Hp2-2 genotype seem to benefit from higher γ-tocopherol concentrations whereas for the other genotype groups there was a direct association with mortality risk.Conclusion Particularly in patients with diabetes mellitus we could show a significant interaction of γ-tocopherol plasma concentration and HP genotype. Carriers of the Hp2-2 genotype seemed to benefit from higher plasma concentrations of γ-tocopherol. Further research is warranted to elucidate the underlying mechanisms and potential therapeutic implications in cardiovascular disease management.