Many bilateral motor tasks engage simultaneous activation of distal and proximal arm muscles, but little is known about their physiological interactions. Here, we used transcranial magnetic stimulation to examine motor-evoked potentials (MEPs), interhemispheric inhibition at a conditioning-test interval of 10 (IHI(10)) and 40 ms (IHI(40)), and short-interval intracortical inhibition (SICI) in the left first dorsal interosseous (FDI) muscle during isometric index finger abduction. The right side remained at rest or performed isometric voluntary contraction with the FDI, biceps or triceps brachii, or the tibialis anterior. Left FDI MEPs were suppressed to a similar extent during contraction of the right FDI and biceps and triceps brachii but remained unchanged during contraction of the right tibialis anterior. IHI(10) and IHI(40) were decreased during contraction of the right biceps and triceps brachii compared with contraction of the right FDI. SICI was increased during activation of the right biceps and triceps brachii and decreased during activation of the right FDI. The present results indicate that an isometric voluntary contraction with either a distal or a proximal arm muscle, but not a foot dorsiflexor, decreases corticospinal output in a contralateral active finger muscle. Transcallosal inhibitory effects were strong during bilateral activation of distal hand muscles and weak during simultaneous activation of a distal and a proximal arm muscle, whereas GABAergic intracortical activity was modulated in the opposite manner. These findings suggest that in intact humans crossed interactions at the level of the motor cortex involved different physiological mechanisms when bilateral distal hand muscles are active and when a distal and a proximal arm muscle are simultaneously active.