To investigate the associations of IkappaBalpha gene polymorphisms with the development and clinical manifestations of systemic lupus erythematosus (SLE), 110 patients with SLE and 120 unrelated healthy controls were enrolled in this study. The IkappaBalpha -881 A/G, -826 C/T, -550 A/T, -519 C/T, and -297 C/T polymorphisms were determined by the polymerase chain reaction/reaction fragment length polymorphism method. The genotype frequency of IkappaBalpha -826 C/T in the patients with SLE was significantly higher than that of the controls (p = 0.003, OR = 2.2, 95% CI = 1.3-3.9). The SLE patients also have significantly higher carriage rate of IkappaBalpha -826 T than the controls (p = 0.01, OR = 2.0, 95% CI = 1.2-3.4). We also found that the estimated haplotype frequency of IkappaBalpha -881A -826T -550A -519C -297C was significantly increased in the patients with SLE in comparison with that of the controls. This study also demonstrated that the association of IkappaBalpha -826 T with SLE was independent of HLA-DR15, which is associated with susceptibility to SLE in Taiwan. Moreover, a synergistic effect could also be found between IkappaBalpha -826 T and HLA-DR15. IkappaBalpha -826 T is associated with the development of SLE in Taiwan. The IkappaBalpha -881A -826T -550A -519C -297C haplotype is also associated with susceptibility to SLE. This study also demonstrated that IkappaBalpha -881G was associated with the occurrence of vasculitis in SLE patients. IkappaBalpha -550T might be a protective factor for the development of malar rash.