Transcranial magnetic stimulation (TMS) to the primary motor cortex (M1) produces a series of corticospinal descending waves, with a direct (D) wave followed by several indirect (I) waves. TMS inducing posterior–anterior (PA) current in the brain predominantly recruits the early I1-wave, whereas anterior–posterior (AP) directed current preferentially recruits the late I3-wave. However, it is not known whether I-waves elicited by different current directions are mediated by the same neuronal populations. We studied the neuronal mechanisms mediating I-waves by examining the influence of short-latency afferent inhibition (SAI) on various I-waves. SAI was tested with electrical median nerve stimulation at the wrist followed by TMS to the contralateral M1 at different current directions. Surface electromyograms and single motor units were recorded from the first dorsal interosseous muscle. SAI was weaker for the AP compared with that for the PA current direction. With increasing median nerve stimulation intensities, SAI increased for the PA direction but showed a U-shaped relationship for the AP direction. SAI produced more inhibition of late I-waves generated by PA than those generated by AP current direction. We conclude that late I-waves generated by PA and AP current directions are mediated by different neuronal mechanisms.