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Hepatotoxicity is the most frequent adverse drug reaction (ADR) in Japanese treated with ticlopidine (TP). We investigated the relationship between CYP2B6haplotype and incidence of TP-induced hepatotoxicity in 114 Japanese patients. Although 4 haplotypes (* 1A,* 1H,* 1Jand *6B) accounted for more than 80% of the inferred haplotypes in both control (n=81) and case (n=22) subjects, the prevalence was apparently different: control, * 1A>*6B>* 1H>* 1Jand case, * 1J>* 1H>* 1A>* 6B.The reporter gene assay for the two SNPs, which comprise the * 1Hor * 1Jhaplotype, suggested that the * 1Hand * 1Jhaplotypes may be associated with the increased expression of CYP2B6, probably due to g. −2320T>C. Combination analysis of CYP2B6and human leukocyte antigen (HLA) haplotypes revealed that individuals possessing CYP2B6* 1Hor * 1Jwith HLA-A*3303have the highest susceptibility to TP-induced hepatotoxicity (odds ratio, 38.82; 95%CI, 8.08-196.0, P<0.001). Although this is a preliminary case-control study with some limitations, it is the first example that HLA-induced idiosyncratic ADR may be modified by individual variation in CYP activities.