This study explored the caregivers' self-reported determinants of antiretroviral therapy (ART) adherence among children under five years living with human immunodeficiency virus (HIV) infection attending Al-Sabah Hospital, South Sudan. Methods: A cross-sectional study of 126 caregivers of HIV-infected children under five years was conducted at Al-Sabah Hospital, South Sudan. Data were collected using an intervieweradministered questionnaire. The self-reported adherence was measured as a binary variable using binary logistic regression. Only variables that were significant at bivariate analysis were analyzed at multivariate level and interpreted using the odds ratios (p< 0.05). Results: Out of 126 caregivers with HIV-infected children, 38 (30.2%) did not adhere to ART. Of the proportion that adhered to ART (88, 69.8%), 49 (55.7%) were male. Most of the children (52, 59.1%) were above two years, but under five years. Fifty (56.8%) of those who adhered had completed 3 months on ART, and the majority were at WHO stage-1 of HIV infection. Analysis of the determinants indicated that children's duration on ART (p=0.001), type of ART regimen (single, double or triple therapy) (p=0.065), type of work done by the caregiver to earn a living (p-value 0.003), time a child was initiated on ART (p=0.002), caregiver-child relationship (p=0.002), caregiver-spousal support (p=0.019), type of support obtained whether monetary or not (p=0.000), when the child was started on ART (p=0.004), the person administering ART (p=0.010), the type of ARVs administered (p=0.001), the caregiver detecting ART side effects (p=0.000), types of adverse effects suffered by the child (p=0.043), time of receiving ART (p=0.047), use of western medicine (p=0.043), healthcare cadre (p=0.002), the kind of attention the healthcare provider offered (p=0.015), and improvements in quality of HIV services (p=0.001) were significantly associated with ART adherence. Conclusion: The study findings indicated that ART adherence among HIV-infected children under five years was suboptimal. This will necessitate continuous engagement and education of caregivers on the prominence of adhering to ART.