Most new HIV infections in sub-Saharan Africa now occur in married and cohabiting couples, many of whom do not realize that only one of them may be infected with HIV. HIV-negative individuals living in stable HIV-discordant partnerships (in which one partner is HIV-infected while the other one is not) are twice as likely to get infected with HIV as those living in concordant HIV-negative relationships. Since HIV transmission occurs mainly from HIV-infected persons who are unaware of their status, a combination of interventions including behavioral and biomedical interventions is urgently needed to increase knowledge of HIV status as well as reduce the risk of HIV transmission within married and cohabiting couples. Behavioral interventions include promotion of couples' counseling, testing and disclosure; condom promotion as well as alcohol risk-reduction, while biomedical interventions include provision of antiretroviral treatment to the HIV-infected partner, medical male circumcision and treatment of sexually transmitted infections. Since no single intervention can turn around the current HIV tide in married and cohabiting couples, we argue for the inclusion of these interventions in a combination prevention package for married and cohabiting HIV-discordant couples in sub-Saharan Africa.