One of the major complications of pregnancy, preeclampsia makes pregnancy term ination inevitable in most cases. Similarities exist between the mechanisms that maintain normal pregnancy, allograft transplants, and, it is postulated, periph eral self-tolerance. In addition, the critical role of the cytotoxic T-lymphoc yte antigen-4 (CTLA-4) molecule in maintaining self-tolerance has been establ ished. Therefore, the frequency of CTLA-4 A49G polymorphism was investigated in severe preeclampsia. Genomic DNA extracted from mononuclear cells of the periph eral blood of 36 pregnant women with severe preeclampsia and 151 healthy women w as analyzed. A49G polymorphism in position 49 of exon-1 of the CTLA-4 gene was studied by the polymerase chain reaction-single-strand conformation polymorph ism (PCR-SSCP) method. The frequency of the GG genotype was 2 (5.6%) in patien ts and 19 (12.6%) in controls, while the frequency of the AA genotype was 4 (11 .1%) and 60 (39.7%). Interestingly, the frequency of the AG genotype was signi ficantly higher in preeclamptic than in healthy women from the general populatio n (83.3%vs. 47.7%; P=0.0005). These data suggest that heterozygosity in the CT LA-4 A49G allele might be a predisposing factor for severe preeclampsia. Whethe r the observed association results from linkage imbalance with other loci on chr omosome 2 or other polymorphisms of the CTLA-4 gene or even from a preferential transfer and/or expression of one allele from a heterozygous mother to the fetu s will be the subject of future investigations. One of the major complications of pregnancy, preeclampsia makes pregnancy term ination inevitable in most cases. In addition, the critical role of The frequency of CTLA-4 A49G polymorphism was investigated in severe preeclampsia. Genomic DNA extracted from mononuclear cells of the periph A49G polymorphism in position 49 of exon-1 of the CTLA-4 gene was studied by the polymerase chain reaction-single-strand conformation polymorph ism (PCR-SSCP The frequency of the GG genotype was 2 (5.6%) in patien ts and 19 (12.6%) in controls, while the frequency of the AA genotype was 4 (11.1%) and 60 (39.7%). Interestingly the freque ncy of the AG genotype was signi ficantly higher in preeclamptic than in healthy women from the general populatio n (83.3% vs. 47.7%; P = 0.0005). These data suggest that heterozygosity in the CT LA- 4 A49G allele might be a predisposing factor for severe preeclampsia. Whethe r the observed association results from linkage imbalance with other loci on chr omosome 2 or other polymorphisms of the CTLA-4 gene or even from a preferential transfer and / or expression of one allele from a heterozygous mother to the fetu s will be the subject of future investigations.