AIM:: To examine the phenotype of mice that lack the adenosine A3 receptor (A3R). METHODS:: We examined the heart rate, body temperature and locomotion continuously by telemetry over several days. In addition, the effect of the adenosine analogue R-N-phenylisopropyl-adenosine (R-PIA) was examined. We also examined heat production and food intake. RESULTS:: We found that the marked diurnal variation in activity, heart rate and body temperature, with markedly higher values at night than during day time, was reduced in the A3R knock-out mice. Surprisingly, the reduction in heart rate, activity and body temperature seen after injection of R-PIA in wild type mice was virtually eliminated in the A3R knock-out mice. The marked reduction in activity was associated with a decreased heat production, as expected. However, the A3R knock-out mice, surprisingly, had a higher food intake but no difference in body weight compared to wild type mice. CONCLUSIONS:: The mice lacking adenosine A3 receptors exhibit a surprisingly clear phenotype with changes in diurnal rhythm and temperature regulation. Whether these effects are due to a physiological role of A3 receptors in these processes or whether they represent a role in development remains to be elucidated.