This study examined the effect of caffeine on self-sustained firing (SSF) of human motor units. At physiological doses, caffeine acts as a competitive antagonist to the inhibitory effects of adenosine. This antagonism has many possible effects on the central nervous system. One of these effects is to increase the release of the excitatory neurotransmitters serotonin and noradrenaline. In addition, caffeine increases serotonin concentration in brainstem regions that have excitatory projections to spinal motor neurons. Since plateau potentials, which are responsible for SSF, are facilitated by these neurotransmitters, we hypothesized that caffeine would increase the frequency at which SSF occurs. A double-blind, repeated-measures design using either drug (6 mg kg(-1) caffeine) or placebo (flour) was carried out on seven male subjects who reported ingesting less than 200 mg week(-1) caffeine. We investigated the occurrence of SSF in tibialis anterior motor units (214 trials) and found a significant (P < 0.05) increase in the occurrence of SSF in the caffeine trial (87.0 +/- 5.8 %) compared to the placebo (64.6 +/- 9.7 %). These data further verify the presence of SSF in the tibialis anterior motor units of young men and provide indirect evidence of the facilitation of plateau potentials by monoamines in the human neuromuscular system.