The role of oxidative stress in the regulation of the copy number of mitochondrial DNA (mtDNA) in human leukocytes is unclear. In this study, we investigated the redox factors in plasma that may contribute to the alteration of mtDNA copy number in human leukocytes. A total of 156 healthy subjects of 25–80 years of age who exhibited no significant difference in the distribution of subpopulations of leukocytes in blood were recruited. Small-molecular-weight antioxidants and thiobarbituric acid reactive substances (TBARS) in plasma and 8-hydroxy-2′-deoxyguanosine (8-OHdG) and 4,977 bp deletion of mtDNA in leukocytes were determined. The mtDNA copy number in leukocytes was determined by real-time PCR. The results showed that the copy number of mtDNA in leukocytes was changed with age in a biphasic manner that fits in a positively quadratic regression model (P=0.001). Retinol (P=0.005), non-protein thiols (P=0.001) and ferritin (P=0.004) in plasma and total glutathione in erythrocytes (P=0.046) were the significant redox factors that correlated with the mtDNA copy number in leukocytes in a positive manner. By contrast, α-tocopherol levels in plasma (P=0.001) and erythrocytes (P=0.033) were negatively correlated with the mtDNA copy number in leukocytes. Three oxidative indices including the incidence of 4,977 bp deletion of mtDNA (P=0.016) and 8-OHdG content in leukocytes (P=0.003) and TBARS in plasma (P=0.001) were all positively correlated with the copy number of mtDNA in leukocytes. Taken these findings together, we suggest that the copy number of mtDNA in leukocytes is affected by oxidative stress in blood circulation elicited by the alteration of plasma antioxidants/prooxidants and oxidative damage to DNA.