Monoamines are powerful modulators of cortical function. Serotonin has complex excitatory and inhibitory effects on animal cortex. Here, the effects of a single oral dose (100mg) of the selective serotonin re-uptake inhibitor sertraline on human motor cortex excitability were investigated in healthy subjects. Transcranial magnetic stimulation was used to test motor threshold, motor evoked potential intensity curve, cortical silent period, paired-pulse inhibition and facilitation and I-wave facilitation. Sertraline resulted in a steeper intensity curve and in depressed paired-pulse facilitation (PPF). All other measures and spinal and neuromuscular excitability remained unaffected. The steeper intensity curve points to an increased excitability of the cortico-spinal neurone, while the depressed PPF suggests an enhanced control of the cortico-spinal neurone by inhibitory interneurones. These features may improve the signal-to-noise ratio of output cells in human motor cortex.