Commercially available polyamidoamine (PAMAM) dendrimer delivery systems, Superfect (SF) and Polyfect (PF) are routinely used as delivery vectors for plasmid DNA and siRNA nucleic acids but are known to have other biological effects. Aside from their drug delivery properties, these cationic PAMAMs, due to differences in their structural architecture, can differentially perturb basal signaling of the epidermal growth factor receptor (EGFR)- a member of the ErbB family of receptor tyrosine kinases that regulates multiple cellular functions. However, little is known of their effects on other members of ErbB family, namely ErbB2, ErbB3 and ErBb4 or on the signaling of EGFR upon stimulation with a ligand or following transactivation via ligand-independent mechanisms. In primary rat aortic vascular smooth muscle cells exposed to 0.4, 4 or 40 µg/ml concentrations of dendrimers for 4h, SF dose-dependently stimulated (up to 2-fold) whereas PF inhibited basal phosphorylation (by approximately 50%) of all ErbB receptors as detected by Western blotting (n=5; p<0.05). Mean values were compared using analysis of variance followed by post hoc test (Bonferroni). Similarly, SF stimulated whereas PF inhibited the activation/transactivation of EGFR by EGF-ligand- (10nM), high-glucose- (25mM) or Angiotensin II (1µM). Similar differential effects of PF and SF on ErbB2, ErbB3 and ErbB4 were also observed in an immortalized human embryonic kidney cells line (HEK-293) implying that this may be a general property related to their structural architecture. AG178, an inhibitor of EGFR phosphorylation, significantly enhanced the inhibitory effects of PF and attenuated SF-induced stimulation of EGFR (p<0.05). Antioxidants (apocynin and tempol) significantly attenuated dendrimer-induced apoptosis and modulation of ErbBs (p<0.05). These data highlight a new biological action of PF and SF PAMAMs in that they can differentially affect the activity of a whole major class of receptor tyrosine kinases (i.e. ErbB family of receptors) via oxidative stress-dependent pathways.