Oxidative stress induces a cellular redox imbalance that has been found to be present in various cancer cells, and overproduction of free radicals may be related to oncogenic stimulation. We investigated the activity of the following antioxidant enzymes: superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and malondialdehyde (MDA) concentrations in blood of patients with head and neck squamous cell carcinoma (HNSCC) compared with the control group. A comet assay was used to assess DNA damage. A nonsignificant increase of MDA and a decrease of SOD, CAT, and GPx (p>0.05) were seen in HNSCC patients compared with controls. It was found that the level of oxidative DNA damage in HNSCC patients was significantly higher compared with the control group (p ≤ 0.001). Our observations suggest that HNSSC patients may represent an impaired antioxidant defense system, resulting in DNA damage and genome instability. It has to be also considered that an oxidant/antioxidant imbalance may be connected to the complex mechanism leading to the DNA damage indicated in the blood of patients with head and neck cancer.