Recently, there has been growing emphasis on enhancing subjective quality of life (QOL), in addition to treating symptoms or extending one's life. However, the neurobiological basis of subjective QOL is unknown. To illuminate the neural substrates that inform subjective QOL, the association between prefrontal function and subjective QOL was explored in 72 healthy volunteers (40 women and 32 men; age, 45.1 ± 20.1 y), using 52-channel near-infrared spectroscopy (NIRS), a portable neuroimaging device that can measure brain function in a less-constrained condition. Results confirmed that subjective QOL was positively correlated with prefrontal hemodynamic response during a cognitive task and that subjective satisfaction regarding social relationships and in the physical domains were cardinal contributors to the association. These findings suggest that subjective QOL has possible involvement in prefrontal function and that NIRS potentially plays a role as a biological marker of subjective QOL.