The association of coffee consumption with the development of increased serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) activities over 4 years was studied in 1221 liver dysfunction-free (serum AST and ALT < or = 39 IU/l and no medical care for or no past history of liver disease) Japanese male office workers aged 35 to 56 years. From the analysis using the Kaplan-Meier method, the estimated incidence of serum AST and/or ALT > or = 40 IU/l, > or = 50 IU/l, and > or = 60 IU/l decreased with an increase in coffee consumption. From the Cox proportional hazards model, coffee drinking was independently inversely associated with the development of serum AST and/or ALT > or = 40 IU/l (p = 0.019 by test for tendency), > or = 50 IU/l (p = 0.002), and > or = 60 IU/l (p = 0.007), controlling for age, body mass index, alcohol intake, and cigarette smoking. These results suggest that coffee may be protectively against the liver dysfunction in middle-aged Japanese men.