BACKGROUND: South Africa accounts for 19% of the global population living with human immunodeficiency virus (HIV), limited knowledge exists on adherence to guidelines when managing complications. AIM: This study assesses regimen adjustment for HIV-positive patients with renal and hepatic dysfunction resulting from antiretroviral therapy (ART) according to the South African Treatment Guidelines and examines the re-initiation of ART in patients who have defaulted. SETTING: The study was conducted at Tshepang HIV Clinic, Ga-Rankuwa, Pretoria, South Africa. METHODS: A retrospective review was conducted between November 2020 and December 2020. Patients who had been on ART for over 18 months and presented with hepatic, renal and/or virological failure were included in the study. The data collection tool included demographics and medical records. Statistical Package for Social Sciences version 25 for Windows was used for data analysis. RESULTS: A total of 181 files were reviewed, and only 37 were eligible for participation. The study found that treatment received by 25% of hepatic failure patients and 41.3% of renal impairment patients complied with South African ART guidelines. Furthermore, 40% of patients with virological failure were re-initiated according to guidelines. CONCLUSION: This study found practices that were contrary to the prescribed guidelines with non-compliance accounting for more than 40%. CONTRIBUTION: This study demonstrates a high incidence of adherence failure to South African ART guidelines. Defaulted patients are placed risk of antiretroviral resistance. Adherence to guidelines is important to prevent complications resulting from ART.