Abstract: Introduction: The etiology of Behcet's disease (BD) is unknown, but like other autoimmune disorders both environmental and genetic factors contribute to its pathophysiology. The familial form of BD is in favor of a genetic predisposition. This study was designed to evaluate the prevalence of the familial form and their possible effect on the disease expression in Iranian patients. Materials & Methods: We studied prospectively 1242 consecutive patients with BD, seen in Behcet's clinic from October 1996 to April 1998. They were classified into two groups according to the presence or absence of a family history of BD. Different manifestations of the disease, including 100 clinical and paraclinical data were compared between the two groups by chi square test and Fisher exact test. A confidence interval at 95% (CI) was calculated for each item. Results: Positive familial history for BD was present in 68 patients (5.5%, CI = 1.3). In 72%, one of the first-degree relatives (parents, children or siblings) was involved. No significant difference was present between the two groups for the mean age (25.1±I0.2 vs. 26.4±9.6 years, p=0.3), the mean disease duration (9.4±6.4 vs. 9.7±7 years, p=0.7) and the mean follow up time (3.3±3.5 vs. 3.5±3.8 years, p=0.7). There was also no statistically significant difference for the presenting signs, although retinal vasculitis and joint involvement were not seen as presenting sign in those with the familial form of the disease. The major clinical manifestations of the disease did not differ between the two groups. Among minor manifestations, only CNS involvement was seen more frequently in familial form of the disease (8.8%± 6.7 vs. 2.7%±0.9, p<0.02). Paraclinical findings, including the pathergy test, showed no significant difference between the two groups. The prevalence of HLA-B5 was not higher in patients with positive familial history of BD (56%±12 vs. 55%±2.8, p=0.87). the presence of HLA-B5 did not increase the incidence of the familial form (5.7%±1.8 vs. 5.3%±1.9, p=0.81). A monozygotic twin brother was seen in this group of patients. A familial positive history for oral aphthosis, but not BD, was present in 607 patients (49%, CI=2.8). The presence of positive familial history for oral aphthosis was slightly higher in familial forms of BD, but without statistically significant difference (53%±11.9 vs. 49%±2.8, p=0.5). Conclusion: The prevalence of positive familial history was 5.5% in Iranian patients with BD. The presence of positive familial history had no effect on the presenting signs, clinical and paraclinical manifestations of the disease, except for a higher prevalence of CNS involvement in familial forms. No relationship seems to exist between positive familial history and B5 genetic background.