The 6-thioguanine resistance (TGr) assay in human T-lymphocytes, which detects mutations at the hprt locus, identifies exposures to environmental mutagens. However, the ability of this assay to detect small increases in mutation rates is limited by the broad range of mutant frequencies (Mf) in healthy individuals. While subject age, lymphocyte cloning efficiency, and cigarette smoking history have been shown to influence the Mf, these factors account for only a portion of the variability in the Mf in human populations. To investigate the influence of dietary differences on hprt Mf, 70 women with breast masses were asked to complete a nutritional questionnaire and submit a peripheral blood sample for a TGr assay. Multivariate analyses, adjusted for age, cloning efficiency and total caloric intake, showed significant positive correlations between vitamin A and iron and InMf (p = 0.03), and a negative correlation between total fat and InMf (p = 0.004). Positive correlations between dietary fiber and copper and InMf, and a negative correlation between alcohol and InMf were of borderline significance (0.05 < or = p < or = 0.07). These results suggest that nutritional components may modulate the hprt Mf. Dietary differences may account for a part of the variability observed in hprt Mf in human populations.