Objective: To investigate whether variation in the HLA-DM gene is important in producing a group of pathogenic autoantibodies—antiphospholipid antibodies (aPL)—on the basis that HLA class II restricted antigen presentation is involved in the production of aPL. Methods: HLA-DMA and DMB polymorphisms were genotyped by polymerase chain reaction combined with restriction enzyme digestion in 51 white patients with primary antiphospholipid syndrome (APS), 82 with systemic lupus erythematosus (SLE) (42 with APS and 40 without APS), and 109 healthy white controls. The association with the aPL profile was examined. Results: The distribution of DMA alleles in APS patients and in patients with APS associated with SLE was significantly different from that in controls by 4x2 χ2 test with 3 degrees of freedom (p = 0.035 and 0.011, respectively), but it was not different between SLE patients without APS and controls. The allelic distribution of DMA was also different between patients with IgG class anticardiolipin antibody or those with lupus anticoagulant (LA) and controls (p = 0.012 and 0.007, respectively) and between patients with and without LA among SLE patients (p = 0.035). All these differences included the increase in DMA*0102 in the former groups. Conclusions: The results suggest that HLA-DMA*0102 or its linked gene(s) form one of the genetic risks for the production of aPL.