BACKGROUND: Integration of depression screening into primary care may increase access to mental health services in sub-Saharan Africa, but this approach requires validated screening instruments. We sought to validate the Patient Health Questionnaire-9 (PHQ-9) as a depression screening tool at a high HIV-burden primary care clinic in Johannesburg, South Africa. METHODS: We conducted a validation study of an interviewer-administered PHQ-9 among 397 patients. Sensitivity and specificity of the PHQ-9 were calculated with the Mini International Neuropsychiatric Interview (MINI) as the reference standard; receiver operating characteristic (ROC) curve analyses were performed. RESULTS: The prevalence of depression was 11.8%. One-third of participants tested positive for HIV. HIV-infected patients were more likely to be depressed (15%) than uninfected patients (9%; p=0.08). Using the standard cutoff score of ≥10, the PHQ-9 had a sensitivity of 78.7% (95% CI: 64.3-89.3) and specificity of 83.4% (95% CI: 79.1-87.2). The area under the ROC curve was 0.88 (95% CI: 0.83-0.92). Test performance did not vary by HIV status or language. In sensitivity analyses, reference test bias associated with the MINI appeared unlikely. LIMITATIONS: We were unable to conduct qualitative work to adapt the PHQ-9 to this cultural context. CONCLUSION: This is the first validation study of the PHQ-9 in a primary care clinic in sub-Saharan Africa. It highlights the potential for using primary care as an access point for identifying depressive symptoms during routine HIV testing. The PHQ-9 showed reasonable accuracy in classifying cases of depression, was easily implemented by lay health workers, and is a useful screening tool in this setting.