We recently demonstrated that an allelic polymorphism in the haptoglobin gene is a major determinant of susceptibility to a number of vascular disorders. We set out to determine if haptoglobin phenotype was predictive of the development of restenosis in a consecutive series of patients, all of whom underwent stent implantation followed by repeat angiography with quantitative coronary angiography analysis 6 months later. This study included 214 consecutive patients undergoing stent implantation for de novo lesions between 1998 and 1999 in Aalst, Belgium. All underwent follow-up quantitative coronary angiography analysis 6 months after the procedure. The haptoglobin phenotype was determined by electrophoresis. No significant differences were found between patients segregated by phenotype with respect to clinical, procedural, and angiographic factors previously suggested to influence the development of restenosis. None of the diabetic patients homozygous for the haptoglobin 1 allele developed restenosis compared with a >50% restenosis rate for diabetic patients with at least 1 haptoglobin 2 allele (p <0.02). In all patients (diabetic and nondiabetic), we observed a trend toward a lower incidence of restenosis in patients homozygous for the 1 allele (21% vs 33%, p <0.09). Moreover, we found a graded risk relation to the number of haptoglobin 2 alleles. The risk of developing restenosis was greater in subjects with 2 haptoglobin 2 alleles (36%) than in those with 1 haptoglobin 2 allele (31%) or no haptoglobin 2 alleles (21%). Thus, knowledge of the haptoglobin phenotype may be useful in assessing and utilizing new therapies that attempt to reduce restenosis, and may have important implications for the risk stratification algorithm used in managing diabetic patients with coronary artery disease.