This qualitative study sought to understand the meaning that women ascribe to living with HIV and symptomatic HSV-2 infections in relationship to their health-related quality of life (HRQoL). HIV affected overall physical and mental HRQoL whereas HSV-2 was an immediate concern experienced on an episodic basis. HSV-2/HIV co-infection was framed as a gendered issue affecting women's abilities to navigate social and sexual relationships and assume social roles. Participants outlined several approaches to overcome their diagnoses and described several social and structural barriers that prevented achieving good HRQoL. HSV-2 is an important medical and psychosocial issue for women living with HIV. Implications for practice and pedagogy are discussed.