Soluble HLA-G (sHLA-G) molecules are found in the peripheral blood of healthy females and males, in cord blood and in amniotic fluids and discussed to be a mediator in maternal-fetal tolerance. In this study we investigated whether there are allele-specific differences in expression of sHLA-G molecules. For this, the sHLA-G plasma concentrations of 94 healthy unrelated individuals were measured by ELISA and correlated to their HLA-G genotypes, as determined by sequence analysis of exon 2 and 3 of the HLA-G gene. Mean sHLA-G levels in individuals with the most common HLA-G alleles G*01011 (27.0+/-2.1 SEM ng/ml, n=66), G*01012 (28.4+/-3.2 SEM ng/ml, n=34) were very similar. In contrast, individuals carrying the HLA-G*01013 (8.1+/-1.7 SEM ng/ml, n=17) or the "null" allele HLA-G*0105N (8.2+/-3.2 SEM ng/ml, n=7) presented significantly (P(c)=0.001 and P(c)<0.01, resp.) reduced sHLA-G levels. Furthermore, individuals with the HLA-G*01041 allele had significantly (P(c)=0.004) increased sHLA-G levels (42.5+/-4.6 SEM ng/ml, n=14). These results demonstrate that the generation of sHLA-G molecules is associated to certain HLA-G alleles and imply that sHLA-G levels are under genetic control. As low and high sHLA-G plasma levels did not segregate with HLA haplotypes including the HLA-G*01013 or *01041 allele, additional mechanisms may be involved in the regulation of the individual sHLA-G levels. Nevertheless, the existence of "low" and "high secretor" HLA-G alleles further suggests different levels of functionality in immune regulation.