Abstract: Introduction: HLA-B51, a split antigen of HLA-B5, has generally been associated with Behcet’s disease (BD) in different countries notably those along the Silk route. The aim of this study was to determine the frequency of HLA-B51 in Iranian patients with BD, and to compare it with the control patients. Patients & methods: In a prospective study, 599 consecutive new patients referred to the BD clinic, in a 9-month period from April 2001 to January 2002, were typed for the presence of HLA-B51 and HLA-B5 serologically. Their frequencies were compared in patients diagnosed BD and those in whom BD was ruled out (control patients). A confidence interval at 95% (CI) was calculated. The comparisons were made by the chi square test. Results: Among the 599 patients, 201 were diagnosed as BD and 398 as control patients. The frequency of B51 was 39% (CI: 6.7) in BD and 18% (CI: 3.8) in controls. The difference was statistically significant (p<0.000001). The frequency of B5 was 48% (CI: 6.9) in BD and 25% (CI: 4.3) in controls, with a statistically significant difference (p<0.000001). The B51 subtype was present in 78% (CI: 8.3) of B5-positive BD patients, and in 69% (CI: 9.1) of B5-positive controls. The difference was not statistically significant (p=0.16). Conclusion: Iranian patients with BD have a higher frequency of both HLA-B51 and HLA-B5 compared to control patients. Although the frequency of B51 subtype was slightly higher in B5-positive BD patients compared to controls, it was not statistically significant.