Objective. In human adipocytes the cAMP-dependent pathway mediates signals originating from beta-adrenergic activation, thus playing a key role in the regulation of important metabolic processes, i.e. lipolysis and thermogenesis. Cyclic AMP effects are mainly mediated by protein kinase A (PKA), whose R2B regulatory isoform is the most expressed in mouse adipose tissue, where it protects against diet-induced obesity and fatty-liver development. Aim of the study was to investigate possible differences in R2B expression, PKA activity and lipolysis in adipose tissues from obese and non-obese subjects. Research Design and Methods. The expression of the different PKA regulatory subunits were evaluated by immunohistochemistry, western blot and real-time PCR in subcutaneous and visceral adipose tissue samples from 20 non-obese and 67 obese patients. PKA activity and glycerol release were evaluated in total protein extract and adipocytes isolated from fresh tissue samples, respectively. Results. Expression techniques showed that R2B was the most abundant regulatory protein, both at mRNA and protein level. Interestingly, R2B mRNA levels were significantly lower in both subcutaneous and visceral adipose tissues from obese than non-obese patients, and negatively correlated with BMI, waist circumference, insulin levels and HOMA-IR. Moreover, both basal and stimulated PKA activity and glycerol release were significantly lower in visceral adipose tissue from obese patients then non-obese subjects. Conclusions. Our results first indicate that in human adipose tissue there are important BMIrelated differences in R2B expression and PKA activation, which might be included among the multiple determinants involved in the different lipolytic response to beta-adrenergic activation in obesity.