It is essential to improve antidepressant treatment of major depressive disorder (MDD) and one way this could be achieved is by reducing the number of treatment steps by employing biomarkers that can predict treatment outcome. This study investigated differences between MDD patients and healthy controls in the P3 and N1 component from the event-related potential (ERP) generated in a standard two-tone oddball paradigm. Furthermore, the P3 and N1 are investigated as predictors for treatment outcome to three different antidepressants. In the international Study to Predict Optimized Treatment in Depression (iSPOT-D)--a multi-center, international, randomized, prospective practical trial--1008 MDD participants were randomized to escitalopram, sertraline or venlafaxine-XR. The study also recruited 336 healthy controls. Treatment response and remission were established after eight weeks using the 17-item Hamilton Rating Scale for Depression. P3 and N1 latencies and amplitudes were analyzed using a peak-picking approach and further replicated by using exact low resolution tomography (eLORETA). A reduced P3 was found in MDD patients compared to controls by a peak-picking analysis. This was validated in a temporal global field power analysis. Source density analysis revealed that the difference in cortical activity originated from the posterior cingulate and parahippocampal gyrus. Male non-responders to venlafaxine-XR had significantly smaller N1 amplitudes than responders. This was demonstrated by both analytical methods. Male non-responders to venlafaxine-XR had less activity originating from the left insular cortex. The observed results are discussed from a neural network viewpoint.