The present study evaluated the relationship between asymmetry of the prefrontal cortex activity and the automatic nervous system (ANS) response during a mental arithmetic (MA) task. Employing near infrared spectroscopy, we compared cerebral blood oxygenation changes in the right and left prefrontal cortices during a mental arithmetic task with HR changes. During the MA task, eight subjects (high-HR group) showed large HR increases (14.2 +/- 3.0) while eight subjects (low-HR group) showed small HR increases (3.6 +/- 2.8) (P < 0.00001). In both the high-HR and low-HR groups, near infrared spectroscopy (NIRS) demonstrated increases of oxyhemoglobin and total hemoglobin (=oxyhemoglobin + deoxyhemoglobin) associated with decreases of deoxyhemoglobin in the bilateral prefrontal cortices during MA task. In the high-HR group, the laterality ratio scores, i.e., [(R - L)/(R + L) of oxyhemoglobin and total hemoglobin], showed positive values (0.17 +/- 0.11 and 0.17 +/- 0.17, respectively), while in the low-HR group, the laterality ratio scores showed negative values (-0.28 +/- 0.21 and -0.35 +/- 0.24, respectively). In addition, there were significant positive correlations between HR changes and the laterality ratio scores of oxyhemoglobin (r = +0.87, P < 0.0001) and total hemoglobin (r = +0.85, P < 0.0001). These results indicate that the MA task-induced activity in the right prefrontal cortex was larger than that in the left prefrontal cortex in the subject with high HR increases, suggesting that the right prefrontal cortex activity during the MA task has a greater role in cerebral regulation of HR by virtue of decreasing parasympathetic effects or increasing sympathetic effects.