The causes for recurrent spontaneous abortion (RSA) remain unknown in a large proportion of the cases. Human leukocyte antigen (HLA)-G and HLA-E are expressed on invasive trophoblast cells, and are supposed to confer to materno-fetal tolerance. A total of 14 different nucleotide sequences have been described for HLA-G, including one dysfunctional null allele (HLA-G*0105N), while five different sequences have been described for HLA-E. In this study, 78 RSA couples and 52 fertile controls were typed for HLA-G and HLA-E by direct sequencing or single strand conformational polymorphism (SSCP) respectively. The overall analysis showed no significant difference in allele frequencies for either HLA-G or HLA-E between the two groups. However, HLA-G allele frequencies in women who had suffered from five or more RSA differed significantly from fertile controls (P: = 0.001), and from women who had undergone three or four RSA (P: = 0.027). Detailed analysis demonstrated a significant increase in the proportion of the HLA-G alleles *01013 and *0105N in the whole group of RSA women compared with fertile controls (P: = 0.007). When studying the prognostic value of HLA genotyping for pregnancy outcome (n = 41), 31 patients (76%) gave birth to a living child without performing immunotherapy. Seven out of 10 (70%) couples suffering from a further RSA carried the HLA-G*01013 or *0105N allele, compared with 10 out 31 (32%) couples giving birth (P: = 0.06). This study suggests that the HLA-G genotype may be a contributing factor in RSA.