The P300 event-related potential (ERP) was elicited in left- and right-handed young adult male and female participants (n = 20/group) with both auditory and visual stimulus discrimination tasks that varied systematically in difficulty. P300 amplitude was larger across all task conditions for left- than for right-handed participants at anterior and central electrode sites. P300 latency was shorter across all task conditions for left- than for right-handers. Task difficulty did not affect the ERP handedness differences. Male and female subjects demonstrated comparable ERP handedness effects, although smaller P300 components were obtained for males than for females. When considered in the context of corpus callosal size differences for left-versus right-handed and male versus female participants, the findings suggest that the P300 reflects callosal size and interhemispheric transmission efficacy.