Introduction In patients with chronic hepatitis C infection, the haptoglobin (Hp) 1-1 phenotype is overrepresented. Data regarding the occurrence of the Cys282Tyr missense mutation in these patients are less clear. We studied the prevalence of both variables in a cohort of patients with chronic hepatitis C and looked for interaction between the two variables. Materials and methods The study group consisted of 142 patients chronically infected with the hepatitis C virus. All patients were examined for the occurrence of the Cys282Tyr missense mutation, and in 132 of them the Hp phenotype was determined.The Cys282Tyr missense mutation was detected by restriction fragment length polymorphism (RFLP) using a standard polymerase chain reaction (PCR) technique and Rsa I digestion. Hp phenotypes were determined using starch gel electrophoresis of haemoglobin-supplemented serum followed by peroxidase staining. Results A significant overrepresentation of the Hp 1-1 phenotype was found (36/132, 27%, P < 0.01 v. control population). This overrepresentation was observed only in the patients homozygous for the wild-type allele of the HFE gene. The Cys282Tyr allele was significantly overrepresented in hepatitis C patients (0.12 v. 0.07, P < 0.05) and principally in patients with the Hp 2-1 and 2-2 phenotypes. Conclusion In patients with chronic hepatitis C infection, both the Hp 1-1 and the Cys282Tyr allele occur more frequently than in a control population. Remarkably, these genes seem to determine each other’s occurrence, such that the overrepresentation of the Hp 1-1 phenotype is seen only in Cys282Tyr-negative subjects, while the overrepresentation of the Cys282Tyr allele is observed in Hp 1-1-negative subjects. Differences in immunomodulating and in oxidative stress-inducing capacities between the two genes may explain this finding. © 2001 Lippincott Williams & Wilkins, Inc.