The Patient Health Questionnaire-2 (PHQ-2) is an ultra-brief questionnaire widely used by researchers and clinicians to detect major depressive disorder (MDD). Despite its individual and societal impact, MDD is often undetected and untreated particularly among sub-Saharan Africans. We conducted this study to evaluate the reliability and validity of using the PHQ-2 as a screen for MDD among Ethiopian adults.A total of 926 adults attending outpatient departments in a major referral hospital in Addis Ababa, Ethiopia participated in this study. Construct validity was assessed by examining associations of PHQ-2 scores with World Health Organization Quality of Life (WHO-QOL) domains. We assessed criterion validity and performance characteristics against an independent, blinded, and psychiatrist administered semi-structured Schedules for Clinical Assessment in Neuropsychiatry (SCAN) interview using measures of sensitivity, specificity and receiver operating characteristics (ROC) curves.The PHQ-2 items showed good reliability (intraclass correlation coefficient=0.92). Quality of life, as reflected by subscale scores for four WHO-QOL domains, was significantly lower among patients with increasing PHQ-2 scores demonstrating good construct validity. ROC analysis and Youden Index showed that a PHQ-2 threshold score of 3 offered optimal discriminatory power with respect to the diagnosis of MDD via the clinical interview (sensitivity=74% and specificity=60%).The Amharic language version of the PHQ-2 had good sensitivity and fair specificity for detecting MDD compared against a psychiatrist administered SCAN diagnosis. This study provides evidence for the PHQ-2 as a reliable and valid ultra-brief screening tool for initial identification of MDD.