Background. There is still limited to no evidence on the independent and interactive effects of HIV infection, disease stage, baseline disease severity and other important comorbidities on mortality risk among young children treated for severe acute malnutrition (SAM) in South Africa (SA, using the World Health Organization (WHO) recommended treatment modality. Objectives. To determine baseline clinical characteristics among children with SAM and assess whether HIV infection, disease stage, critical illness at baseline and other comorbidities independently and interactively contributed to excess mortality in this sample.Methods. We followed up children aged 6 - 60 months, who were admitted with and treated for SAM at two rural hospitals in SA, and retrospectively reviewed their treatment records to abstract data on their baseline clinical characteristics and treatment outcomes. In total, 454 children were included in the study. Descriptive statistical tests were used to summarise patients’ clinical characteristics. Kaplan-Meier failure curves were created for key characteristics and compared statistically using log-rank tests. Univariate and multivariate Cox regression was used to estimate independent and interactive effects. Results. The combined case fatality rate was 24.4%. HIV infection, clinical disease stage, the presence of lower respiratory tract infection, marasmus and disease severity at baseline were all independently associated with excess mortality. The critical stage for higher risk of death was when cases were admitted at WHO stage III. The interactions of two or three of these characteristics were associated with increased risk of death when compared with having none, with HIV infection and critical illness showing the greatest risk (hazard ratio 22, p<0.001). Conclusion. The high HIV prevalence rate in the study setting and the resultant treatment outcomes support the notion that the WHO treatment guidelines should be revised to ensure that mechanisms for effective treatment of HIV comorbidity in SAM are in place. However, a much more rigorous study is warranted to verify this conclusion.