In this study the transcriptomic profiling of adenosine receptors (ARs) in human leukocytes of heart failure (HF) patients as a function of clinical severity, assessing the possible changes with respect to healthy subjects (C), was evaluated. Total RNA was extracted from leukocytes ofC(n=8) and of HF patients (NYHA I-IIn=9; NYHA III-IVn=14) with a PAXgene Blood RNA Kit. An increase as a function of clinical severity was observed in each AR (A1R:C=0.02±0.009, NYHAI-II=0.21±0.09, NYHAIII-IV=3.6±1.3,P=0.03 Cversus NYHA III-IV,P=0.02NYHA I-II versus NYHA III-IV; A2aR:C=0.2±0.05, NYHAI-II=0.19±0.04, NYHAIII-IV=1.32±0.33,P=0.005 Cversus NYHA III-IV,P=0.003NYHA I-II versus NYHA III-IV; A2bR:C=1.78±0.36, NYHAI-II=1.35±0.29, NYHAIII-IV=4.07±1.21,P=0.03: NYHA I-II versus NYHA III-IV; A3R:C=0.76±0.21, NYHAI-II=0.94±0.19, NYHAIII-IV=3.14±0.77,P=0.01 Cversus NYHA III-IV and NYHA I-II versus NYHA III-IV, resp.). The mRNA expression of the ectonucleoside triphosphate diphosphohydrolase (CD39) and the ecto-5′-nucleotidase (CD73) were also evaluated. They resulted up-regulated. These findings show that components of adenosine metabolism and signalling are altered to promote adenosine production and signalling in HF patients. Thus, HF may benefit from adenosine-based drug therapy after confirmation by clinical trials.