With the hypothesis that depression affects memory through a mechanism other than that of the benzodiazepines, the present study evaluated the acute effect of diazepam 10 mg upon explicit memory in patients with major depression. A double-blind, placebo (starch 50 mg) controlled experiment was carried out with 19 patients randomly divided into diazepam (n = 10) and placebo (n = 9) groups. They were evaluated by the Mini-Mental State Examination, and tests were conducted for immediate and delayed (short-term) memory with emotionally toned stimuli (negative, positive, neutral), recognition, and semantic memory in visual or auditory modality. The Visual Analog Mood scale (VAMS) was applied to measure anxiety and mood changes after the administration of drugs (30 minutes and 6 hours). Higher scores in the positively toned list among patients who received diazepam were observed, at the 30-minute compared with the 6-hour evaluation. The recall index of positive words in the diazepam group was positive and significantly different from the index of the placebo group. No anterograde amnesia following diazepam was observed. The neural model of a dysfunction of limbic prefrontal cortical structures that impairs the modulation of the amygdala in major depression may explain the present results. Consequently, the action of diazepam on the amygdala, which has been proposed to be the basis of its anxiolytic action, might be altered, modifying the modulation of memory in our patients