A lmadori et al. reported decreased serum folate and increased homocysteine concentrations in patients with head and neck carcinoma compared with healthy nonsmokers or smokers. 1 The authors concluded that these metabolic alterations might promote or derive from disease progression. Similarly, decreased serum folate and increased homocysteine concentrations were observed earlier in patients with colorectal carcinoma. 2 Folic acid is the source of the coenzymes participating in onecarbon metabolism in the synthesis of thymidine or purines. Therefore, folate is required for DNA and RNA biosynthesis and thus for cell proliferation. The reduced folate derivative methyl-tetrahydrofolate participates in the methylation of homocysteine to form methionine. Because of this latter association, inadequate availability of the vitamin underlies the development of moderate hyperhomocysteinemia, which has been reported to be a risk factor for cardiovascular disease, stroke, and thrombosis. 3 An inverse relation usually exists between homocysteine and folate concentrations and, accordingly, folate supplementation is believed to be well able to correct hyperhomocysteinemia. 3 In patients with various types of malignancy, increased neopterin concentrations were found to be predictive of a worse prognosis (e.g., in squamous cell carcinoma of the oral cavity). 4 Elevated neopterin levels are believed to indicate immune activation and oxidative stress emerging from activated macrophages, and in a broad variety of diseases, increased neopterin levels coincide with moderate hyperhomocysteinemia. 5 Methyl-tetrahydrofolate, the biologically active cofactor of the conversion of homocysteine to methionine, is very susceptible to oxidation, a factor that may become relevant under oxidative stress conditions. Immune system-derived oxidative stress appears to be crucial for folate depletion resulting in hyperhomocysteinemia, even when dietary folate is within the recommended range. 5 The findings of Almadori et al. suggest that decreased folate and increased homocysteine also might coexist with increased neopterin concentrations in patients with squamous cell carcinoma of the head and neck, 1 which would support the view that hyperhomocysteinemia in patients with carcinoma of the head and neck is an indirect consequence of hyperconsumption of antioxidant vitamins during prolonged states of immune activation. In this instance, folate deficiency and hyperhomocysteinemia are unlikely to be primary in the pathogenesis of squamous cell carcinoma. Rather, malignant cells may evoke an immune response, and hyperhomocysteinemia would result from an increased demand for vitamins that develops in a variety of diseases associated with long-lasting immune activation and oxidative stress.