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In August 2011, South Africa expanded its adult antiretroviral therapy (ART) guidelines to allow treatment initiation at CD4 cell values 350 cells/μl or less. Mortality and morbidity are known to be reduced when initiating at higher CD4 levels; we explored the impact on patient loss to follow-up.An observational cohort study.We analyzed routine data of 1430 adult patients initiating ART from April to December 2010 from a Johannesburg primary healthcare clinic offering ART initiation at CD4 cell count 350 cells/μl or less since 2010. We compared loss to follow-up (≥3 months late for the last scheduled visit), death, and incident tuberculosis within 1 year of ART initiation for those initiating at CD4 cell values 200 or less versus 201–350 cells/μl.Half (52.0%) of patients presented in the lower CD4 cell group [≤200 cells/μl, median: 105 cells/μl, interquartile range (IQR): 55–154] and initiated ART, and 48.0% in the higher group (CD4 cell count 201–350 cells/μl, median: 268 cells/μl, IQR: 239–307). The proportion of women and pregnant women was greater in the high CD4 cell group; the lower CD4 cell group included more patients with prevalent tuberculosis. Among men and nonpregnant women, initiating at 201–350 cells/μl was associated with 26–42% reduced loss to follow-up compared to those initiating 200 cells/μl or less. We found no CD4 cell effect among pregnant women. Risk of mortality [adjusted hazard ratio (aHR) 0.34, 95% confidence interval (CI) 0.13–0.84] and incident tuberculosis (aHR 0.44, 95% CI 0.23–0.85) was lower among the higher CD4 cell group.This is one of the first studies from a routine clinical setting to demonstrate South Africa's 2011 expansion of ART treatment guidelines can be enacted without increasing program attrition.