Introduction During pregnancy, the maternal immune system must cope with the semi-allogeneic fetus in order to facilitate a successful pregnancy. The extra-villous trophoblast cells situated at the feto-maternal interface express high amounts of the immune regulatory non-classical human leukocyte antigen-G (HLA-G). A 14 base pair insertion/deletion polymorphism (14 bp ins/del) in the 3″-untranslated region of the HLA-G gene has an impact on the expression level of HLA-G and a low expression of HLA-G have been linked to pregnancy complications like preeclampsia. Objectives In the present study, we investigated the impact of the fetal HLA-G 14 bp ins/del genotype on the clinical outcome in normal pregnancies and pregnancies complicated by preeclampsia, in terms of birth weight and placental weight of children born by mothers heterozygous for the HLA-G 14 bp ins/del. Patients and methods Two independent cohorts of pregnant women were used for this nested case-control study. Analysis were made on pregnancies complicated by severe preeclampsia (n = 101), normal uncomplicated pregnancies (n = 185) and a combination of the two. Both Taqman analyses and DNA sequencing were applied to determine the HLA-G 14 bp ins/del genotype. Results Combining normal pregnancies and pregnancies complicated by preeclampsia and adjusting for gestational age at birth, the results show that newborns born by HLA-G 14 bp heterozygous mothers that are homozygous for the HLA-G 14 bp insertion, have a significantly lower birth weight (P = 0.008) and lower placental weight (P = 0.009) compared to newborns that are homozygous for the HLA-G 14 bp deletion. The results indicate that children with the HLA-G 14 bp ins/ins genotype born by mothers suffering from severe preeclampsia have a lower birthweight than children with the HLA-G 14 bp ins/del or del/del genotypes born by mothers suffering from severe preeclampsia, however not significantly (P = 0.08). Conclusion The highest mean birth weight and placenta weight was observed in newborns homozygous for the HLA-G 14 bp deletion and the lowest mean birth and placenta weight was observed in newborns homozygous for the HLA-G 14 bp insertion. It can be speculated that a compromise between intermediate birth and placenta weight, HLA heterozygosity and induction of maternal tolerance have evolved in humans.