In resource-limited settings, holding regimens such as lamivudine monotherapy (LAM) have been used to manage HIV-positive children failing combination antiretroviral therapy to mitigate the risk of drug resistance developing, while adherence barriers are addressed or when access to second- or third-line regimens is restricted. South African HIV treatment guidelines previously advocated the use of LAM to manage HIV-infected children with virological failure. However, the outcomes of patients on LAM compared with those who continued on a failing regimen have not been well described. Objectives. To investigate characteristics of a large cohort of children placed on LAM and their outcomes. Methods. This was a retrospective review of children with virological failure and the documented M184V drug resistance mutation who were placed on LAM v. a control group of children who continued on a failing regimen despite persistent virological failure. Virological and immunological outcomes of LAM were compared with those in patients who remained on a failing regimen. Results. A total of 179 children were included in the analysis, with 92 in the LAM group and 87 in the control group. The median (interquartile range (IQR)) age at baseline was 9.2 (5.4 - 12) years, the median CD4 count was 384 (184 - 622) cells/μL, and the median HIV viral load was 4.7 (IQR 3.7 - 5.3) log10. Twenty-two children (25.6%) in the LAM group and 15 (17.4%) in the control group experienced immunological deterioration. There was no statistical difference between the two groups with regard to overall time to immunological deterioration (log-rank p-value 0.4810). Conclusion. Given that a higher proportion of children in the LAM group experienced immunological failure, the LAM strategy may be a useful short-term one but should be restricted to children with limited treatment options. Managing children with virological failure will continue to be a challenge until improved adherence strategies are available.