We looked for brain perfusion abnormalities in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). An initial pilot study revealed widespread reduction of regional brain perfusion in 24 ME/CFS patients, compared with 24 normal volunteers. Hypoperfusion ofthe brainstem (0.72±0.05 vs. 0.80±0.04, p<0.0001) was marked and constant. We then tested whether perfusion to the brainstem in ME/CFS patients differs from thatin normals, patients with major depression, and others with epilepsy. Data from a total of 146 subjects were included in the present study: 40 normal volunteers, 67 patients with ME/CFS(24 in the pilot study, 16 with no psychiatric disorders, 13 with ME/CFS and depression, 14 with ME/CFS and other psychiatric disorders), 10 epileptics, 20 young depressed patientsand 9 elderly depressed individuals. Brain perfusion ratios were calculated using ⁹⁹Tc^m-hexamethylpropylene amine oxime (⁹⁹Tc^m- HMPAO) and single-photon emission tomography (SPET) with a dedicated three-detector gamma camera computer/system (GE Neurocam). Brainstem hypoperfusion was confirmed in all ME/CFS patients. Furthermore, the 16 ME/CFS patients with no psychiatric disorders and the initial 24 patients inthe pilot study showed significantly lower brainstem perfusion (0.71$0.03) than did depressed patients (0.77$0.03; ANOVA, p<0.0001). Patients with ME/CFS have a generalized reduction of brain perfusion, with a particular pattern of hypoperfusion of the brainstem.