This study investigated the relationship between highly active antiretroviral therapy (HAART) and instrumental activities of daily living (IADLs) among two clinical cohorts in South Africa. Between 2003 and 2008 structured questionnaires were administered to HIV-positive patients attending outpatient clinics at an urban hospital (Soweto, n = 3,081) and a rural hospital (Acornhoek, n = 1,247). Among those receiving help, an average of 4.8 and 5.1 h of assistance with IADLs daily was reported (rural and urban participants, respectively), with the patient's mother and children assisting the most. Participants on HAART were 17 and 41% less likely to receive assistance with IADLs in the rural and urban cohorts, respectively, after adjusting for demographic characteristics, healthcare utilization, and CD4 counts. HAART significantly decreased the IADL assistance among patients in South Africa. Alongside clinical benefits, HAART has the potential to reduce the burden of HIV-related care, potentially extending wider social and economic gains to other family members.