Animal studies have provided direct evidence that dietary factors induce changes in DNA methylation patterns. In humans, studies on diet and DNA methylation have yielded inconsistent findings. Because humans tend to consume foods and nutrients that are highly interrelated, study of dietary patterns may have improved the power of detecting the effect of diet on DNA methylation. Using data collected from 149 participants aged 45-75 y in the North Texas Healthy Heart Study, we examined the relationship between dietary patterns and levels of genomic DNA methylation in peripheral blood leukocytes. Dietary data were collected from study participants using the Block FFQ. Genomic DNA methylation was measured using bisulfite conversion of DNA and real-time PCR (MethyLight) for LINE-1. Two dietary patterns were identified using factor analysis: a " prudent" dietary pattern characterized by a high intake of vegetables and fruits, and a " Western" dietary pattern characterized by a high intake of meats, grains, dairy, oils, and potatoes. The prudent dietary pattern was associated with a lower prevalence of DNA hypomethylation (Q4 vs. Q1; OR = 0.33, 95% CI: 0.12-0.92) and the association was dose dependent (P-trend = 0.04). There was no apparent association between the Western dietary pattern and global leukocyte DNA methylation (Q4 vs. Q1; OR = 1.28, 95% CI: 0.47-3.47; P-trend = 0.55). Thus, a dietary pattern characterized by a high intake of vegetables and fruits may protect against global DNA hypomethylation. Future studies with a larger sample size need to confirm that this association holds longitudinally.