Health services in sub-Saharan Africa are under great pressure to provide adequate clinical care due to the continued HIV epidemic, and nurse-driven models of care are one means to address physician shortages. This case-control study examines the reasons for and correlates of patient referral from nurses to physicians at HIV primary care clinics in South Africa prior to initiating antiretroviral treatment. Ninety-seven HIV-infected cases who required physician consolation and 160 controls who did not require physician consultation (matched on gender, age, and date of clinic visit) were consecutively enrolled at both an urban and rural HIV primary care clinic during a 12-month period beginning in March 2006. Univariate and multivariate logistic regression models were used to assess correlates of patient referral to a physician. Cases were more likely to have lower CD4 cell counts and have WHO Stages III and IV disease compared to controls (p<0.05). Predictors of patient referral were a CD4 cell count between 50 and 200 cells/µl (adj OR: 5.27, 95% CI: 2.16-12.88, p<0.0001), a CD4 cell count below 50 cells/µl (adj OR: 3.47, 95% CI: 1.12-10.78, p=0.032), and Stage IV disease (adj OR: 4.58, 95% CI: 1.35-15.60, p=0.015). Additionally, the following ICD-10 clinical diagnoses were associated with patient referral: tuberculosis, aplastic and other anemias, and lower respiratory tract infection (p<0.05). Nurses can provide adequate clinical and diagnostic management for certain clinical conditions to HIV-infected patients. Further studies are needed to examine specifically how HIV healthcare delivery can be scaled-up in resource-limited settings with a high burden of HIV, but with a minimal healthcare infrastructure.