Superantigen is characterized as a potent stimulator of T cells through its unique interaction with major histocompatibility complex class II molecule and the V beta chain of T cell receptor. It has been reported that symptoms in several infectious diseases are associated with superantigen activity, i.e., abnormal reaction due to excess activation of T cells. However, the implications of superantigen in human immunodeficiency virus (HIV) infections have not been well elucidated. In this article, we review the possible mechanisms by which superantigens may modify HIV infections. In conclusion, superantigen is considered to be a factor that aggravates the immunodeficient state in HIV-infected patients through activation of HIV expression in infected T cells and monocytes, and facilitation of CD4 T cell depletion. Since exogenous superantigen is most likely to be provided by microbial infections such as Staphylococcus aureus infection, countermeasures against these complicating infections may be important to avert the detrimental impact of superantigens.