Human leukocyte antigen (HLA)-G is an MHC class Ib molecule that is expressed at the feto-maternal interface during pregnancy. However, recent results have also shown that it may have important functions as an immuno-modulatory factor in adult life. Differences in the pattern of alternative splicing and in the stability of HLA-G mRNA transcripts have been associated with HLA-G polymorphisms, especially a 14 bp deletion/insertion polymorphism in the 3' untranslated region of the HLA-G gene. We have investigated the secretion of HLA-G5/soluble HLA-G1 and interleukin-10 (IL-10) in lipopolysaccharide (LPS)-activated peripheral blood mononuclear lymphocytes (PBMCs) in relation to the HLA-G 14 bp genotype. No HLA-G5/sHLA-G1 could be detected in the non-activated control PBMC culture media, and there were no significant differences among the three HLA-G 14 bp genotypes regarding IL-10 concentrations. In LPS-activated PBMC cultures, no significant differences among the three HLA-G 14 bp genotypes regarding HLA-G5/sHLA-G1 concentrations were observed. However, this was in contrast to the IL-10 levels (P=0.0004, Kruskal-Wallis test). The +14/+14 bp PBMC samples expressed higher levels of IL-10 when compared to the -14/+14 bp genotype and the -14/-14 bp genotype. Interestingly, the IL-10 G/G polymorphism at position -1082 was more frequent in the +14/+14 bp genotype (P=0.024, chi2 test). These results support an autocrine loop between HLA-G5/sHLA-G1 and IL-10 expression in activated PBMCs, which may result in higher IL-10 levels in +14/+14 bp HLA-G genotypes.