Recently, 2 physiologically distinct phases of short-interval intracortical inhibition (SICI) have been identified, a larger phase at interstimulus interval (ISI) 3 ms and a smaller phase at ISI 1 ms. While the former is mediated by synaptic processes, the mechanisms underlying the first phase of SICI remain a matter of debate. Separately, it is known that fatiguing hand exercise reduces SICI, a measure of cortical excitability. Consequently, the present study assessed effects of fatiguing hand exercise on the 2 SICI phases, using threshold tracking transcranial magnetic stimulation techniques, to yield further information on underlying mechanisms. Studies were undertaken on 22 subjects, with SICI assessed at baseline, after each voluntary contraction (VC) period of 120 s and 5, 10, and 20 min after last VC, with responses recorded over abductor pollicis brevis. Exercise resulted in significant reduction of SICI at ISI 1 ms (SICI(baseline) 9.5 ± 2.7%; SICI(MAXIMUM REDUCTION) 2.5 ± 2.5%, P < 0.05) and 3 ms (SICI(baseline) 16.8 ± 1.7%; SICI(MAXIMUM REDUCTION) 11.6 ± 2.1%, P < 0.05), with the time course of reduction being different for the 2 phases. Taken together, findings from the present study suggest that synaptic processes were the predominant mechanism underlying the different phases of SICI.