Testing for random mating at an HLA locus is a difficult problem becau
se of the highly polymorphic nature of the HLA loci. We discuss some m
ethodological issues and propose several tests. A simulation study is
conducted to evaluate these tests. The single allele test and the shar
ed allele test deal with small sample sizes by aggregating the data in
different ways. The shared allele test is found to be a more powerful
method of detecting non-random mating patterns involving a deficiency
or an excess of similar genotypes than the single allele test. We sho
w that random mating of couple at the genotype level implies the rando
m mating of couple at the allele level. Several multi-allele approache
s are proposed for large population-based data sets. Among them, the c
orrected allele-table test performs better than the generalized Wald t
est in terms of power and size. These methods are then applied to an H
LA data set of Caucasian couples, and no solid evidence for non-random
mating at the HLA A, B, and DR loci is found.