The role of dietary one-carbon determinants remains largely unexplored for non-Hodgkin's lymphoma (NHL). In a population-based case-control study of non-African-American adult (aged 20-74 years) women and men from four US Surveillance, Epidemiology, and End Results study centers (Detroit, Michigan; Iowa; Los Angeles, California; and Seattle, Washington; 1998-2000), the authors examined folate; vitamins B2, B6, and B12; methionine; and a one-carbon antagonist, alcohol, in 425 incident NHL cases and 359 controls who completed a detailed food frequency questionnaire. Adjusted odds ratios and 95% confidence intervals were estimated by using unconditional logistic regression. Higher intake of one-carbon determinants from food was associated with a lower risk of NHL, but that for only vitamin B6 (highest vs. lowest quartile: odds ratio = 0.57, 95% confidence interval: 0.34, 0.95; p trend = 0.01) and methionine (odds ratio = 0.49, 95% confidence interval: 0.31, 0.76; p trend = 0.002) reached statistical significance. Folate from food was inversely associated with diffuse subtype (odds ratio = 0.47, 95% confidence interval: 0.23, 0.94; p trend = 0.03). The authors found no association between total (food plus supplement) vitamins and NHL. Nonusers of alcohol had an elevated NHL risk compared with users, and alcohol did not modify other nutrient-NHL associations. Findings suggest that one-carbon nutrients, particularly vitamin B6 and methionine, may be protective against NHL.