Despite the efficacy of selective serotonin reuptake inhibitors (SSRIs) in the treatment of major depression, a significant number of patients show partial or no remission of symptoms. Some evidence suggests that psychostimulant augmentation may be helpful in treating patients with residual symptoms of depression. The efficacy of modafinil in augmenting SSRIs in depressed patients with residual fatigue or excessive daytime sleepiness has yet to be systematically investigated. In a series of 25 patients with major depressive disorder, according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, who showed significant residual symptoms after an adequate SSRI trial (12 wk) and who were evaluated according to the Fatigue Severity Scale (FSS), subjects with scores > or = 4 were given open-label modafinil augmentation for a minimum of an additional 6 wk. Treatment response was assessed prospectively with the FSS, the Epworth Sleepiness Scale (ESS), and the Hamilton Rating Scale for Depression (HAM-D) during the first visit and at the second and sixth weeks. Twenty-one of 25 patients in this series who were treated with modafinil and SSRIs completed the 6-wk augmentation trial. At end-point assessment, all patients showed significant improvement in fatigue and sleepiness in FSS and ESS scores, as well as in HAM-D scores (P<.01). In the second week, 29.4% of patients had a HAM-D score <7, which was defined as remission; this rate was 64.7% in the sixth week. The rate of patients whose HAM-D score dropped by more than 50%, defined as responders to treatment, was 41.1% and 76.4% in the second and sixth weeks, respectively. Results of this preliminary, open-label trial suggest that modafinil may be effective in augmenting ongoing SSRI treatment for a portion of patients with major depression who have residual fatigue and sleepiness. Larger, placebo-controlled trials appear warranted to investigate the clinical efficacy and tolerability of modafinil augmentation of SSRI treatment in these patients.