During sustained, fatiguing maximal voluntary contraction of muscles of one hand, muscles of the other hand gradually become activated also. Such effort-induced mirror movements indicate a decreased ability of the central nervous system (CNS) to selectively control individual muscles. We studied whether altered transcallosal inhibition (TCI) contributed to this phenomenon. TCI was determined in ten healthy subjects by measuring the ipsilateral silent period (iSP) and the contralateral silent period (cSP) during a sustained contraction of the abductor digiti minimi, induced by focal unihemispheric ipsilateral transcranial magnetic stimulation. Mirror movements occurred in all subjects in response to the effort. There was a bilateral increase in cSPs and a parallel increase in the iSP in the contralateral working muscle. In contrast, the iSP in the mirroring muscle remained unchanged, explained by a balance of increased crossed pyramidal inhibition (cSP) and decreased transcallosal inhibition. In finely tuned unimanual movements, mirroring activity of the contralateral hand is suppressed by TCI originating in the working hemisphere. During sustained, effortful contractions, the outflow of the contralateral hemisphere is increased due to reduced TCI. Effort-induced mirror contractions are thus the result of disinhibition of contralateral crossed projections rather than disinhibition of ipsilateral uncrossed pathways.