Background Haptoglobin (Hp) is an abundant plasma protein with antioxidant properties. The Hp 2‐2 genotype has previously been linked to coronary heart disease risk in individuals with elevated glycosylated hemoglobin (HbA _1c ). We investigated the association of Hp and HbA _1c with cardiovascular disease ( CVD ) in the longitudinal, population‐based Bruneck Study. Methods and Results Hp genotype was determined by polymerase chain reaction according to standard procedures and HbA _1c concentration by a Diabetes Control and Complications Trial‐aligned assay. HbA _1c was measured in 1995, 2000, and 2005. Occurrence of the combined CVD endpoint of myocardial infarction or stroke was recorded between 1995 and 2010. Outcome analyses employed the Cox proportional hazards model with HbA _1c category as time‐varying covariate. At baseline in 1995, 806 subjects (male sex, 49.3%; age, mean±standard deviation, 62.70±11.08 years) were included. During follow‐up, 123 subjects experienced at least 1 CVD event (48 suffered myocardial infarction, 68 stroke, and 7 both). Among subjects with HbA _1c ≥6.5% (≥48 mmol/mol), those with the Hp 2‐2 genotype did not show an elevated risk of incident CVD compared with those with other genotypes (age‐ and sex‐adjusted hazard ratio [95% CI ], 0.47 [0.19, 1.13], P =0.092) and a null association was also observed in subjects with HbA _1c <6.5% (1.10 [0.75, 1.62], P =0.629) ( P for interaction=0.082). Conclusions Subjects with the Hp 2‐2 genotype and elevated HbA _1c compared with subjects with other Hp genotypes and elevated HbA _1c did not show increased CVD risk.