BACKGROUND: A major barrier to accessing free government-provided antiretroviral treatment (ART) in South Africa is the shortage of suitably skilled health professionals. Current South African guidelines recommend that only doctors should prescribe ART, even though most primary care is provided by nurses. We have developed an effective method of educational outreach to primary care nurses in South Africa. Evidence is needed as to whether primary care nurses, with suitable training and managerial support, can initiate and continue to prescribe and monitor ART in the majority of ART-eligible adults.METHODS/DESIGN:This is a protocol for a pragmatic cluster randomised trial to evaluate the effectiveness of a complex intervention based on and supporting nurse-led antiretroviral treatment (ART) for South African patients with HIV/AIDS, compared to current practice in which doctors are responsible for initiating ART and continuing prescribing. We will randomly allocate 31 primary care clinics in the Free State province to nurse-led or doctor-led ART. Two groups of patients aged 16 years and over will be included: a) 7400 registering with the programme with CD4 counts of [less than or equal to] 350 cells/mL (mainly to evaluate treatment initiation) and b) 4900 already receiving ART (to evaluate ongoing treatment and monitoring). The primary outcomes will be time to death (in the first group) and viral suppression (in the second group). Patients' survival, viral load and health status indicators will be measured at least 6-monthly for at least one year and up to 2 years, using an existing province-wide clinical database linked to the national death register.TRIAL REGISTRATION:Controlled Clinical Trials ISRCTN46836853