There is increasing interest in the use of brief screening tools to improve detection of depression in the primary care setting. The aim of the present study was to compare the accuracy of the two-item Patient Health Questionnaire (PHQ-2) against the nine-item Patient Health Questionnaire (PHQ-9) for detecting depression among general practice patients. A cross-sectional sample of 3626 adults attending 12 Australian general practices was recruited. Participants completed the PHQ-2 and PHQ-9 via a touchscreen computer. Depression was defined as a PHQ-9 score ≥10. The area under the curve (AUC), sensitivity, specificity, positive predictive value and negative predictive value were calculated. The PHQ-2 had good overall accuracy relative to the PHQ-9 for discriminating between cases and non-cases of depression, with an AUC of 0.92 (95% confidence interval 0.90-0.93). The PHQ-2 threshold of ≥3 was the best balance between sensitivity (91%) and specificity (78%) for detecting possible cases of depression. For clinical use, the optimal threshold was ≥2, with only 2% of possible cases missed.