Caffeine increases time to fatigue (TLIM) during submaximal isometric contractions without altering whole muscle activation or neuromuscular junction transmission. We used 10 male volunteers in a randomized, double blind, repeated-measures experiment to examine single motor unit firing rates during intermittent submaximal contractions and to determine if administering caffeine increased T_LIM by maintaining higher firing rates. On two separate days, subjects performed intermittent 50% maximal voluntary contractions (MVC) of the quadriceps to T_LIM, 1 h after ingesting a caffeine (6 mg/kg) or placebo capsule. Average motor unit firing rates recorded with tungsten microelectrodes were constant for the duration of contractions. Caffeine increased average T_LIM 20.5 ± 8.1% (p < 0.05) compared to placebo conditions. This increase was due to seven subjects, termed responders, who increased T_LIM significantly. Two other subjects showed no response and a third had a shorter TLIM. Neither the increased T_LIM nor the responders' performance could be explained by alterations in firing rates or other neuromuscular variables. However, the amplitude of the evoked twitch and its maximal instantaneous rate of relaxation (-dF/dt) did not decline to the same degree in the caffeine trial of the responders; this resulted in values 20 and 30% higher at the time point matching the end of the placebo trial (p < 0.05). The amplitude of the evoked twitch and the maximal instantaneous rate of relaxation were linearly correlated (caffeine r = 0.72, placebo r = 0.80, both p < 0.001), suggesting that the increase in TLIM may be partially explained by caffeine's effects on Ca²⁺-reuptake and twitch force.