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Herpes simplex virus type 2 (HSV-2) and syphilis are associated with HIV infection. The purpose of this review is to summarize the advances in the relationship of HSV-2 and syphilis with HIV, highlighting intervention trials to prevent HIV acquisition and transmission.HIV acquisition has often been linked to genital ulcers due to HSV-2 and syphilis. The latest pathophysiological studies have continued to elucidate the relationship between HSV-2, syphilis and HIV, establishing that both syphilitic and HSV-2-infected tissue have increased numbers of chemokine receptor 5-expressing T cells, and several models have further emphasized the viral synergy between HSV-2 and HIV. In clinical trials, HSV suppressive therapy decreased HIV RNA levels that might affect transmission, but two trials have failed to prevent HIV acquisition. Male circumcision, however, prevents both HIV and HSV-2 acquisition.Genital ulcers from HSV-2 and syphilis are associated with HIV acquisition. The exact role for these HIV cofactors is still unknown and exemplified by the failure of HSV suppressive therapy to decrease HIV acquisition. Male circumcision, however, reduces HSV-2 acquisition. With several HSV suppressive trials to prevent HIV transmission and disease progression currently ongoing, the future promises to provide more critical information for the control of HIV infection.