Genetic factors that could mediate the pathogenesis of male reproductive disorders are largely unclear. Polymorphisms of cytochrome P4501A1 (CYP1A1), a key enzyme in the extrahepatic metabolism of lipophilic xenobiotics, have been shown to influence susceptibility to xenobiotics. Here, CYP1A1 polymorphisms were investigated in 134 infertile Caucasian men. The frequencies of the Mspl polymorphism in the 3'-flanking region of the CYP1A1 gene and a mutation in exon 7 causing an isoleucine-valine exchange (IVE) in the heme-binding region of the enzyme were increased among infertile men when compared with those of unselected, healthy male controls (odds ratio (OR)) 1.4, Cl95 0.68-2.89 for Mspl polymorphism; OR 2.4, Cl95 0.83-6.95 for IVE). Patients with normozoospermia revealed the highest frequencies for both polymorphisms (n = 8; OR 4.5, Cl95 0.97-20.91 for Mspl polymorphism; OR 13.7, Cl95 2.53-74.13 for IVE). ORs for the IVE exceeded the values calculated for the Mspl polymorphism. These preliminary results suggest that genetic variation in the metabolism of xenobiotics may codetermine individual susceptibility to infertility.