Background: Medication-resistant depression (MRD) is associated with poorer attentional performance and immense socioeconomic costs. Aims: We aimed to investigate the central pathophysiology of MRD, previously linked to impaired prefrontal cortex function. Method: A total of 54 participants (22 with MRD, 16 with non-resistant depression, 16 healthy controls) were recruited. Non-MRD status was confirmed by a prospective 6-week antidepressant trial. All medication-free participants underwent a go/no-go task to study prefrontal cortical function (attention) and positron emission tomography scans to study regional cerebral glucose metabolism (rCMglu) at rest. Results: The MRD group had worse attentional ratings and decreased rCMglu compared with the non-MRD and control groups. Attentional performance was positively associated with prefrontal cortex rCMglu. The prefrontal cortex differences between MRD and non-MRD groups remained after adjusting for past depressive episodes (F(1,35) = 4.154, P = 0.043). Conclusions: Pronounced hypofrontality, with the associated attentional deficits, has a key role in the neuropathology of medicationresistant depression. Declaration of interest: None.