BACKGROUND: In high-income countries, depression is prevalent in HIV patients and is associated with lower medication adherence and clinical outcomes. Emerging evidence from low-income countries supports similar relationships. Yet little research has validated rapid depression screening tools integrated into routine HIV clinical care. METHODS: Using qualitative methods, we adapted the Patient Health Questionnaire-9 (PHQ-9) depression screening instrument for use with Cameroonian patients. We then conducted a cross-sectional validity study comparing an interviewer-administered PHQ-9 to the reference standard Composite International Diagnostic Interview in 400 patients on antiretroviral therapy attending a regional HIV treatment center in Bamenda, Cameroon. RESULTS: The prevalence of major depressive disorder (MDD) in the past month was 3% (n=11 cases). Using a standard cutoff score of ≥10 as a positive depression screen, the PHQ-9 had estimated sensitivity of 27% (95% confidence interval: 6-61%) and specificity of 94% (91-96%), corresponding to positive and negative likelihood ratios of 4.5 and 0.8. There was little evidence of variation in specificity by gender, number of HIV symptoms, or result of a dementia screen. LIMITATIONS: The low prevalence of MDD yielded very imprecise sensitivity estimates. Although the PHQ-9 was developed as a self-administered tool, we assessed an interviewer-administered version due to the literacy level of the target population. CONCLUSION: The PHQ-9 demonstrated high specificity but apparently low sensitivity for detecting MDD in this sample of HIV patients in Cameroon. Formative work to define the performance of proven screening tools in new settings remains important as research on mental health expands in low-income countries.