During fatiguing exercise corticomotor excitability increases as force declines, which may serve to increase motor output to the exercising muscle, but paradoxically at the same time there is an increase in silent period (SP) duration which is thought to represent a build-up of intracortical inhibition. Paired-pulse TMS at long interstimulus intervals can also be used to derive an index of long-interval cortical inhibition (LICI), however this has not yet been investigated in fatigue. Our aim was to measure LICI during and after a fatiguing exercise and determine if the changes in the index of LICI parallel the changes in SP duration. To do this, we used single and paired-pulse TMS to measure motor evoked potential (MEP) amplitude, LICI and SP duration during, and for 10 min after, a 10-min intermittent maximal fatiguing exercise of the index finger, designed to fatigue the first dorsal interosseous (FDI) muscle (force after 10-min of exercise 64 +/- 7% of baseline, P < 0.05). Single-pulse MEP amplitude and SP duration were increased during fatiguing exercise (minute 10; 179 +/- 24% and 128 +/- 9% of baseline, respectively, P < 0.05), in contrast the measure of LICI was reduced compared to baseline (minute 10; 0.45 +/- 0.17 vs. baseline; 0.70 +/- 0.10, P < 0.05). These results suggest that SP duration and LICI may reflect processes occurring in different neuronal populations. The increased SP duration may correspond to processes of central fatigue in centres 'upstream' of primary motor cortex (M1), whereas the decrease in LICI, together with increased MEP amplitude, are consistent with an increase in M1 output during fatigue that may serve to compensate for reduced central drive.