Introduction: For clients on HIV treatment in sub-Saharan Africa, disengagement from HIV care in the early treatment period is a critical obstacle to achieving UNAIDS's second 95 target. While South Africa's Differentiated Service Delivery Guideline on Fast Track Initiation and Counseling (FTIC) define normative procedures, the effect of guideline implementation and the underlying drivers of disengagement remain unclear. Methods: The PREFER mixed-methods study enrolled a prospective cohort of adult clients initiating ART, returning to care after a period of disengagement or already on ART for <6 months at 18 public sector healthcare facilities in South Africa. A survey collected data on demographic and clinical characteristics and preferences of participants who were followed up through routinely-collected medical visit records for up to 7 months after treatment initiation to estimate continuity of HIV care (attended all scheduled visits within 28 days). Focus group discussions (FGDs) were conducted approximately 12 months after enrollment among a subset of participants who had expressed concerns about treatment retention. Results: During the study period 7/9/2022-30/6/2023, PREFER-SA enrolled 1,049 participants (72% female, median age=33 years, 24% with CD4 count<200 cells/mm3); 122 of whom also participated in focus group discussions. By 6 months on ART, 23% were not continuously in HIV care. Those newly initiating ART at study enrollment were more likely to have disengaged or interrupted treatment by 6 months as those who had remained in care for >1 visit. Disengagement was also more likely among men and younger (18-24 years) participants, those reporting food scarcity, and those initiated on regimens other than Dolutegravir. Disengagement did not differ by gender, relationship status, or CD4 count. Qualitative FGD results suggest participants experience barriers to adherence within and between all levels of the socio-ecologic model. Challenges related to the facility experience were most prominent. Conclusions: Among adults initiating or re-initiating ART in South Africa, the highest risk of disengagement is immediately after initiation. We identified several potentially modifiable individual and social characteristics associated with early disengagement. Improving the patient facility experience and strengthening implementation of SA's Service Delivery Guidelines may increase retention during the early treatment period.