Research has shown that long-term exposure to lead harms the hematological system. The homeostatic iron regulator HFE mutation, which has been shown to affect iron absorption and iron overload, is hypothesized to be related to lead intoxication in vulnerable individuals. The aim of our study was to investigate whether the HFE genotype modifies the blood lead levels that affect the distributions of serum iron and other red blood cell indices. Overall, 121 lead workers and 117 unexposed age-matched subjects were recruited for the study. The collected data included the blood lead levels, complete blood count, serum iron, total iron binding capacity, transferrin and ferritin, which were measured during regular physical examinations. All subjects filled out questionnaires that included demographic information, medical history, and alcohol and tobacco consumption. HFE genotyping for C282Y and H63D was determined using polymerase chain reaction and restriction fragment length polymorphism (PCR/RFLP). The mean blood lead level in lead workers was 19.75 ug/dL and was 2.86 ug/dL in unexposed subjects. Of 238 subjects, 221(92.9%) subjects were wild-type (CCHH) for HFE C282Y and H63D, and 17 (7.1%) subjects were heterozygous for a H63D mutation (CCHD). Multiple linear regression analysis showed that blood lead was significantly negatively associated with hemoglobin (Hb), mean corpuscular hemoglobin concentration (MCHC), and mean corpuscular volume (MCV), whereas the HFE variant was associated negatively with MCV and positively with ferritin. An interactive influence on MCV was identified between blood lead and HFE variants. Our research found a significant modifying effect of the HFE variant, which possibly affected MCV. The HFE H63D heterozygous (CCHD) variant seemed to provide a protective factor against lead toxicity. Further study on competing binding proteins between iron and lead influenced by gene variation is needed for future studies.