Previous studies have shown that changes in brain function precede clinical response to antidepressant medications. Here we examined quantitative EEG (QEEG) absolute and relative power and a new measure, cordance, for detecting regional changes associated with treatment response. Fifty-one adults with unipolar depression completed treatment trials using either fluoxetine or venlafaxine vs. placebo. Data were recorded at baseline and after 48 h and 1 week on drug or placebo. Baseline and change from baseline values were examined for specific brain regions in four subject groups (medication and placebo responders and nonresponders). No regional baseline QEEG differences were found among the groups; there also were no significant changes in theta power over time. In contrast, medication responders uniquely showed significant decreases in prefrontal cordance at 48 h and 1 week. Clinical differences did not emerge until after four weeks. Subjects with greater changes in cordance had the most complete 8-week responses. These findings implicate the prefrontal region in mediating response to antidepressant medications. Cordance may have clinical applicability as a leading indicator of individual response.