Objective The purpose of this study is to compare the diagnostic accuracy of four depression screening tools commonly used in patients with medical disorders, relative to a reference diagnostic standard—a structured psychiatric interview. Methods The Depression in the Medically Ill-18 (DMI-18) questionnaire was administered to 167 patients with medical disorders; of those, 53 completed the Beck Depression Inventory for Primary Care (BDI-PC), 67 the Hospital Anxiety and Depression Scale (HADS), and 46 the Patient Health Questionnaire-9 (PHQ-9). The entire sample was also interviewed with a structured psychiatric interview conducted by a mental health professional. Sensitivity, specificity, likelihood ratios (LRs), and area under the curve (AUC) were calculated and compared for the different measures. Results At their respective recommended cutoff points, sensitivities [95% confidence interval (CI)] were 86% (70–95), 82% (63–94), 93% (86–97), and 68% (47–85) for the HADS-D, BDI-PC, DMI-18, and PHQ-9, respectively, while specificities ranged from 72% (47–90) for BDI-PC to 89% (72–98) for PHQ-9. The sensitivities of DMI-18 were significantly higher compared to those of HADS-D (P=.045) and PHQ-9 (P=.01). The PHQ-9 questionnaire obtained the most favorable positive LR (6.35; 95% CI, 2.48–18.36). In contrast, the DMI-18 showed the best negative LR (0.09; 95% CI, 0.04–0.18). Areas under the curves (95% CI) ranged from 0.92 (0.83–1.02) to 0.84 (0.74–0.94). Statistically significant differences were found between the AUCs of the DMI-10 and the BDI-PC. Conclusion Our results suggest that all evaluated scales have acceptable abilities and can be used as screening instruments for depression in patients with medical disorders. The DMI stands out for its sensitivity.