Prior investigations have reported that changes in the prefrontal electroencephalogram (EEG) precede symptom improvement from antidepressant medications, and could serve as a biomarker of treatment outcome in major depressive disorder (MDD). A new physiologically defined region of interest (ROI), overlying the midline and right frontal (MRF) cortical area, was examined here for a relationship between early decreases in theta-band cordance and remission. Subjects were 72 adults with unipolar MDD who had completed placebo-controlled antidepressant treatment trials, with 37 randomized to medication and 35 to placebo. We assessed changes in cordance and absolute and relative power in the MRF region at 48 h, 1 week, and 2 weeks after start of drug, as potential predictors of remission (final score on the 17-item Hamilton Depression Rating Scale of 5 or below. Out of 37 medication-treated subjects, 11 (30%) remitted versus 6 of 35 placebo subjects (17%). Change in MRF cordance 1 and 2 weeks after the beginning of treatment was significantly associated with remission in medication-treated subjects at 1 week, with receiver operating characteristic (ROC) analysis yielding 0.76 area under the curve. Decreases in MRF cordance at 1 week predicted remission with medication with 69% overall accuracy (90% sensitivity; 60% specificity). MRF cordance changes were not associated with remission with placebo. Absolute and relative power did not differentiate groups. These results suggest that remission may be predictable from physiologic measurements after 1 week of treatment, and that this region merits further investigation in the neurobiology of treatment response.