RING 11, a second transport-associated gene (TAP2), has been recently identified in the DR-DP interval of the human class II region. Two predominant alleles, TAP2A and TAP2B, differing by 17 amino acids at the C-terminus of the ATP-binding domain are present in the Caucasoid population at frequencies of 79% and 21%, respectively. In the rat, polymorphism of the TAP genes were found to influence peptide loading of MHC class I molecules and, in humans, it was speculated that variation in peptide loading of HLA-B27 molecules might be also linked to factors altering antigen presentation presumably encoded in the HLA region. To determine whether TAP2 gene polymorphism may be relevant to peptide loading in humans, we typed 41 HLA-ABC, DR-identical pairs for TAP2A and TAP2B by PCR-SSO hybridization or direct genomic sequencing. In eight cases, GLO-different and, in six cases, DP-different recombinant siblings were included. Allele frequencies for TAP2A and TAP2B were as previously reported (74% and 26%, respectively). In all pairs, TAP2 gene polymorphism segregated with the DR-DQ type, mapping the TAP2 gene telomeric to the recombination hot spot in the DR-DP interval of the human class II region. We conclude that, in HLA-identical siblings, TAP2 gene differences are very unlikely to occur. Thus, in HLA-identical siblings, minor histocompatibility antigenic differences cannot be attributed to variant peptide loading due to TAP2 gene polymorphism.