Background The pericardial fluid May be representative of the interstitium of the heart. The aim of this study was to discriminate in cardiovascular disease patients between adipocytokines that are produced locally by the heart and those supplied by the circulation. Methods Enzyme-linked immunosorbent assays (ELISA) were used to determine levels of N-terminal pro-brain natriuretic peptide (NT-pBNP), fatty acid-binding protein 4 (FABP4), leptin, lipocalin-2, neutrophil elastase, proteinase-3, high sensitivity C-reactive protein (hsCRP) and adiponectin in venous plasma and pericardial fluid harvested during elective cardio-thoracic surgery (n = 132–152). Results In pericardial fluid compared to plasma, the levels were significantly smaller (p < 0.001) for leptin, lipocalin-2, neutrophil elastase, proteinase-3, hsCRP and adiponectin. For these biomarkers, the ratio of pericardial fluid-to-plasma level ([PF]/[P], median (interquartile range)) was 0.65 (0.47–1.01), 0.78 (0.56–1.09), 0.23 (0.11–0.60), 0.17 (0.09–0.36), 0.14 (0.08–0.35), and 0.25 (0.15–0.34), respectively. In contrast, pericardial fluid was significantly enriched (p < 0.001) in NT-pBNP ([PF]/[P]: 1.9 (1.06–2.73)) and even more so for FABP4 ([PF]/[P]: 3.90 (1.47–9.77)). Moreover, in pericardial fluid, the adipocytokines interrelated all significantly positive and correlated negative to hsCRP, whereas for NT-pBNP only a significantly positive correlation with adiponectin was found. These interrelations were distinct from those in the plasma, as were the correlations of the pericardial biomarkers with patient characteristics compared to plasma. Conclusions In cardiovascular disease patients, the pericardial cavity is a distinct adipocytokine microenvironment in which especially FABP4 is mainly derived from the heart.