Aims The present study aimed to phenotype the cerebral structural and glucose metabolic alterations in patients with heart failure (HF) using simultaneous positron emission tomography (PET)/magnetic resonance (MR) and to investigate their relationship to cardiac biomarkers and cognitive performance.Methods and results Forty-two HF patients caused by ischaemic heart disease (mean age 67.2 +/- 10.4, 32 males) and 32 age- and sex-matched healthy volunteers (mean age 61.3 +/- 4.8, 18 males) were included in this study. Participants underwent simultaneous cerebral fluorine-18 (18F) fluorodeoxyglucose PET/MR followed by cardiac MR scan, and neuropsychological scores were obtained to assess cognitive performance. The grey matter volume (GMV) and standardized uptake value ratio (SUVR) were calculated to examine cerebral structural and metabolic alterations. Cardiac biomarkers included cardiac MR parameters and cardiac serum laboratory tests. Mediation analysis was performed to explore the associations among cerebral alterations, cardiac biomarkers, and cognitive performance. HF patients demonstrated notable cognitive impairment compared with normal controls (P < 0.001). Furthermore, HF patients exhibited regional brain hypometabolism in the bilateral calcarine cortex, caudate nucleus, thalamus, hippocampus, precuneus, posterior cingulate cortex, lingual and olfactory cortex, and GMV reduction in bilateral thalamus and hippocampus (cluster level at P < 0.05, Gaussian random field correction). The SUVR of the hypometabolic brain regions was correlated with the Montreal Cognitive Assessment (MoCA) scores (r = 0.55, P = 0.038) and cardiac stroke volume (r = 0.49, P = 0.002). Cerebral hypometabolism played a key role in the relationship between the decreased stroke volume and MoCA scores, with a mediation effect of 33.2%.Conclusions HF patients suffered cerebral metabolic and structural alterations in regions associated with cognition. The observed correlation between cardiac stroke volume and cognitive impairment underscored the potential influence of cerebral hypometabolism, suggesting that cerebral hypometabolism due to chronic systemic hypoperfusion may significantly contribute to cognitive impairment in HF patients.