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Objective: Coffee consumption has been related to decreased risk of type 2 diabetes, but it is unclear whether this relation is affected by cytochrome P450 1A2 (CYP1A2), a primary enzyme of caffeine metabolism. We examined the associations of two functional genetic polymorphisms of CYP1A2 with glucose tolerance status and the effect modification of the CYP1A2 polymorphisms on the association between coffee and impaired glucose metabolism . Methods: The subjects were 2263 male officials aged 46-59 years in the Self-Defense Forces in Japan. Individual glucose tolerance status was classified into normal glucose tolerance, Impaired Fasting Glycemia (IFG), Impaired Glucose Tolerance (IGT) or type 2 diabetes by a 75 g oral glucose tolerance test. IFG and IGT were combined as a single entity (IFG/IGT). Coffee consumption was assessed by a self-administered questionnaire. The CYP1A2 polymorphisms (CYP1A2*1C and CYP1A2*1F) were genotyped by the PCR-RFLP method. Results: Neither CYP1A2*1C nor CYP1A2*1F showed a measurable association with IFG/IGT or type 2 diabetes. Coffee consumption was inversely associated with IFG/IGT and type 2 diabetes. The inverse association between coffee and type 2 diabetes was significant in the GG genotype of CYP1A2*1C , but not in the GA and AA genotypes combined (interaction P=0.07). This effect modification was more evident among smokers (interaction P=0.03). Neither of the two polymorphisms modified the association between coffee and IFG/IGT. Conclusions: The CYP1A2*1C polymorphism modified the association between coffee and type 2 diabetes, especially among current smokers, suggesting that caffeine may not be negligible in the coffee-diabetes association.