Whereas the genetic risk for type 1 diabetes is linked to human leukocyte antigen (HLA) class II genes, the HLA association in type 2 (non-insulin-dependent) diabetes is less clear. The association between HLA class II genotypes and type 2 diabetes was examined in adult Bahrainis, an Arab population with a high prevalence of type 2 diabetes. HLA-DRB1* and -DQB1* genotyping of 86 unrelated type 2 diabetes patients (age, 51.6+/-8.2 years; mean duration of diabetes, 7.7+/-7.1 years) who had a strong family history of diabetes (52 of 72 versus 0 of 89 for controls, P<0.001) and 89 healthy subjects was done by PCR-sequence-specific priming. DRB1*040101 (0.1221 versus 0.0562, P=0.019) and DRB1*070101 (0.2151 versus 0.0843, P<0.001) were positively associated, while DRB1*110101 (0.0698 versus 0.1461, P=0.014) and DRB1*160101 (0.0640 versus 0.1236, P=0.038) were negatively associated with type 2 diabetes. DRB1*040101-DQB1*0302 (0.069 versus 0.0007; P=0.004), DRB1*070101-DQB1*0201 (0.178 versus 0.0761, P=0.007), DRB1*070101-DQB1*050101 (0.125 versus 0.0310, P=0.002), and DRB1*150101-DQB1*060101 (0.0756 versus 0.0281, P=0.008) were more prevalent among patients, while DRB1*160101-DQB1*050101 (0.0702 versus 0.0349, P=0.05) was more prevalent among controls, conferring disease susceptibility or protection, respectively. In Bahrainis with type 2 diabetes, there is a significant association with select HLA class II genotypes, which were distinct from those in type 1 diabetes.