Pre-eclampsia affects 2-7% of all pregnancies with varying severity and is a leading cause of maternal and fetal mortality and morbidity. The aetiology involves almost certainly a combination of genetic predisposition with maternal and fetal contributions and environmental factors. Research points towards pathologies in the placenta as the triggering factor which leads to systemic endothelial dysfunction in the mother, probably as the result of interaction with released placental factors circulating in the maternal blood. One prominent hypothesis regarding the aetiology of pre-eclampsia suggests that it is caused by immune- maladaptation. The MHC class Ib gene, HLA-G, is expressed in the placenta and seems to have immunomodulatory functions. Aberrant HLA-G mRNA and protein expression in pre-eclamptic placentas have been reported. Here, we have investigated detailed HLA-G genotypes in a case-control study of 155 family triads of mother, father and newborn. Among primiparas, an overrepresentation of a homozygous HLA-G genotype was detected in the 40 pre-eclamptic offspring compared to the 70 controls [P = 0.002, Fisher's exact test; odds ratio 5.57 (95% CI 1.79-17.31)]. Further analyses suggested that the differences between pre-eclamptic cases and controls primarily were accomplished by a different transmission from the father of a 14 bp deletion/insertion polymorphism in exon 8 (P = 0.006, Fisher's exact test), which previously has been linked to differences in the levels of HLA-G expression and in HLA-G mRNA splicing. The results may also indicate that combined mother-child HLA-G genotypes could influence the risk of developing pre-eclampsia. Overall, the study suggests that HLA-G genotypes and expression might have a significant influence on development of pre-eclampsia.