BACKGROUND. Cigarette smokers are known to have lower concentrations of circulating ascorbic acid than nonsmokers. In contrast, there is evidence that the extracellular fluid lining of the alveolus, which comes in close contact with cigarette smoke, and the alveolar macrophages of smokers are enriched with ascorbic acid. The clinical significance of these observations is unknown. METHODS. The authors measured the ascorbic acid concentrations and radiolabeled methyl incorporation (which is inversely related to the degree of DNA methylation in vivo) of paired samples of squamous cell carcinoma (SCC) and adjacent uninvolved mucosa of the lung and larynx (n = 22). RESULTS. Cancerous tissues had significantly higher ascorbic acid concentrations (mean ± standard deviation [SD, 485 ± 77; median, 483 ng/mg protein) compared with their matched uninvolved tissues (mean ± SD, 151 ± 52; median, 72 ng/mg protein; P < 0.0001). The radiolabeled methyl incorporation was significantly higher in cancerous tissues (mean ± SD, 31,419 ± 2629; median, 31,416 counts per minute [CPM]/μg DNA) compared with their matched uninvolved tissues (mean ± SD, 11,883 ± 1567; median, 11,444 CPM/μg DNA; P < 0.0001). The Spearman correlation between ascorbic acid concentrations and radiolabeled methyl incorporation by DNA in SCCs was inverse and statistically significant (r = -0.58, P = 0.008), indicating a beneficial effect of accumulated ascorbic acid in global methylation of DNA. In the uninvolved tissues, this correlation was inverse but statistically not significant (r = -0.20, P = 0.35). CONCLUSIONS. Cancerous tissues of the lung and larynx demonstrated their ability to accumulate ascorbic acid. The accumulation of ascorbic acid by these tissues seemed to facilitate global methylation of DNA. (C) 2000 American Cancer Society.