Nicotinic acetylcholine receptor stimulation is a potential target for controlling symptoms in several psychiatric disorders. Galantamine is a cholinesterase inhibitor that can modulate the nicotinic receptor sites. In this study, we examined the effect of galantamine on the quantitative EEG in patients with major depression. Twenty patients were included in a randomized, double-blinded, placebo-controlled trial. Patients received galantamine (8 mg/day for 4 weeks then 16 mg/day for another 4 weeks) or placebo for eight weeks. Quantitative EEG using the international 10 to 20 configuration, 9 minutes of resting, eyes closed, and eyes open was done before and after the study period. Nineteen patients completed the study and their data were included in the final analysis. The results showed that galantamine compared with placebo reduced absolute band power that was statistically significant (using multivariate analysis of variance) for beta wave [F(1,17) = 2.48, P = 0.03]; the between-subject effect was significant on the left and right posterior, and left central regions. The multivariate analysis of variance model for alpha was not significant [F(1,17) = 1.07, P = 0.43]. We suggest that the reduction in absolute power after galantamine administration could be a sign of brain activation as a result of modulation of neurotransmitter release. We recommend the initiation of a larger study to confirm our findings and help in understanding the neuropathology of major depression.