Genetic susceptibility to type 1 autoimmune hepatitis is indicated by a preponderance of female subjects and strong associations with human leukocyte antigens (HLA) DRB1*0301 and DRB1*0401. The gene encoding cytotoxic T-lymphocyte antigen-4 (CTLA-4) on chromosome 2q33 may also influence autoimmunity. To determine the frequency and significance of the exon 1 adenine (A)-guanine (G) base-exchange polymorphism for CTLA-4 in patients with type 1 autoimmune hepatitis, 155 northern European Caucasoid patients and 102 ethnically-matched control subjects were tested by polymerase chain reaction. The genotype distribution was significantly different in patients compared to controls (AA β«Ψβ¬ 50/155 patients vs. 51/102 controls; AG β«Ψβ¬ 84/155 patients vs. 38/102 controls; GG β«Ψβ¬ 21/155 patients vs. 13/102 controls, 2 β«Ψβ¬ 8.94, P β«Ψβ¬ .011). This difference was caused by a significant over-representation of the G allele in patients compared to controls (105/155 patients vs. 51/102 controls, 2 β«Ψβ¬ 8.34, P β«Ψβ¬ .004, odds ratio β«Ψβ¬ 2.12). The GG genotype was associated with a significantly higher mean serum aspartate transaminase level (P β«Ψβ¬ .03), greater frequency of antibodies to thyroid microsomal antigens (P β«Ψβ¬ .004) and was found more commonly in patients with HLA DRB1*0301 (P β«Ψβ¬ .02). Treatment outcomes, however, were not affected by the genotype. The CTLA-4 G allele is more common in patients with type 1 autoimmune hepatitis and may represent a second susceptibility allele. Furthermore, there may be synergy between the HLA-DRB1*0301 and the GG genotype in terms of disease risk. (HEPATOLOGY 2000;31:49-53.) Autoimmune hepatitis (AIH) is an unresolving hepatocellular inflammation of unknown cause. The diagnosis requires the presence of interface hepatitis on histological examination, hypergammaglobulinemia, abnormally elevated serum