The authors conducted this investigation to study the effects of interstimulus interval duration for a given simple visual reaction time trial on the relationship between lead exposure and reaction time. Organolead manufacturing workers (n=222) and nonexposed referents (n=62) were administered a neurobehavioral test battery that included simple visual reaction time. Simple visual reaction time was measured over 44 trials; interstimulus intervals ranged from 1 to 10 s in a randomly generated sequence that was identical for all study subjects. Mean reaction times for both lead-exposed and nonexposed subjects were longest for interstimulus intervals of 1 and 2 s. Mean reaction times in response to moderate (4-6 s) and long (7-10 s) interstimulus intervals were mainly associated with lead exposure; this association led the authors to suggest that interstimulus interval duration modifies the relationship between lead exposure and simple visual reaction time performance. In simple visual reaction time protocols, stronger associations between reaction time and lead exposure may be found if the analysis trials are separated with interstimulus intervals of less than 3 s duration.