Objective: To examine whether the rate of HLA similarity among 609 primarily infertile couples is higher than would be expected by chance. Design: Clinical Trial. Subjects: 609 primary infertile couples (mean age women: 34.35 years, men: 37.59 years) were recruited before undergoing IVF or ICSI therapy. Couples with former pregnancies, tubal factor, azoospermia or donor therapies were excluded. Intervention: For each of the partners, exons encoding the corresponding antigen recognition sites of HLA-A, −B, −C, −DRB1, −DQB1, and −DPB1 were sequenced by using next-generation sequencing. HLA similarity between partners was determined based on the probability of homozygous offspring and the observed probability of heterozygous offspring in the sample of primary infertile couples was comparted to the probability for random pairing using bootstrapping. Main outcome measures: HLA similarity of infertile couples compared to randomly assigned couples. Results: In each of the loci, infertile pairs shared more alleles than expected by chance. This result was significant for all HLA class 2 loci (−DRB1, −DQB1, −DPB1), as well as for the HLA class I locus −C, while HLA-A and −B showed a nonsignificant trend towards higher similarity. Conclusion: These data suggest that HLA similarity between couples relates to primary infertility.