The health consequences of coffee drinking remain controversial. We report on an association between coffee consumption and the concentration of total homocysteine (tHcy) in plasma, a risk factor for cardiovascular disease and for adverse pregnancy outcome. The study population consisted of 7589 men and 8585 women 40-67 y of age and with no history of hypertension, diabetes, ischemic heart disease, or cerebrovascular disease. They were recruited from Hordaland county of western Norway in 1992-1993. Daily use of coffee was reported by 89.1% of the participants, of whom 94.9% used caffeinated filtered coffee. There was a marked positive dose-response relation between coffee consumption and plasma tHcy, which was stronger than the relation between coffee and total serum cholesterol. In 40-42-y-old men, mean tHcy was 10.1 mumol/L for nonusers and 12.0 mumol/L for drinkers of > or = 9 cups of coffee/d. Corresponding tHcy concentrations in 40-42-y-old women were 8.2 and 10.5 mumol/L, respectively. Although coffee drinking was associated with smoking and lower intake of vitamin supplements and fruit and vegetables, the coffee-tHcy association was only moderately reduced after these variables were adjusted for. The combination of cigarette smoking and high coffee intake was associated with particularly high tHcy concentrations. A strong inverse relation between tea and tHcy concentration in univariate analysis was substantially attenuated after smoking and coffee drinking were adjusted for. The results of the present report should promote future studies on tHcy as a possible mediator of adverse clinical effects related to heavy coffee consumption.