Single dose administration of efficacious antidepressant agents elicit characteristic pharmaco-electroencephalographic (EEG) profiles in healthy volunteers but acute and chronic pharmaco-EEG profiling of antidepressant action in depressed patients has been relatively lacking. This study sought to examine the quantitative topographic EEGs of depressed patients in response to paroxetine treatment. Thirty male patients, meeting DSM-IV criteria for major depression, were examined before and after a single 20 mg dose. These, and an additional 40 patients, were also assessed following 6 weeks of treatment. Eyes-closed resting EEG, collected from 21 scalp sites, was spectrally analyzed to yield regional measures of absolute/relative power and mean frequency in delta, theta, alpha, beta and total spectrum frequency bands. Chronic treatment resulted in a significant reduction in scores on the Hamilton Rating Scale for Depression (HAM-D), with 80% of treatment completers exhibiting a >50% reduction in depression ratings at the end of the 6th week. Acute paroxetine did not alter EEG in patients but chronic treatment was associated with significant alterations as shown by diffuse decreases in alpha power and increases in slow (delta and theta) and anterior fast (beta) wave power, Mean theta and alpha (occipital) frequency were slowed while mean total frequency was accelerated at frontal sites and decreased at occipital sites. The chronic pharmaco-EEG response pattern reflects both sedating and activating actions in regional specific areas which are relevant to the pathophysiology and the pharmacotherapeutic treatment of depression.