Family history (FH) is predictive of the development of major psychiatric disorders (PSY). Familial psychiatric disorders are largely a consequence of genetic factors and typically exhibit more severe impairments. Decreased prefrontal activity during verbal fluency testing (VFT) may constitute an intermediate phenotype for PSY. We investigated whether familial PSY were associated with a greater severity of prefrontal dysfunction in accordance with genetic loading. We measured prefrontal activity during VFT using near-infrared spectroscopy (NIRS) in patients with schizophrenia (SCZ, n = 45), major depressive disorder (MDD, n = 26) or bipolar disorder (BIP, n = 22) and healthy controls (HC, n = 51). We compared prefrontal activity among patients with or without FH and HC. Patients in the SCZ, MDD and BIP patient groups had lower prefrontal activity than HC subjects. Patients with and without FH in all diagnostic groups had lower prefrontal activity than HC subjects. Moreover, SCZ patients with FH had lower prefrontal activity than SCZ patients without FH. When we included patients with SCZ, MDD or BIP in the group of patients with PSY, the effects of psychiatric FH on prefrontal activity were enhanced. These findings demonstrate the association of substantially more severe prefrontal dysfunction with higher genetic loading in major psychiatric disorders.