ErbB3 is an important regulator of tumorigenesis and is implicated in development of resistance to several currently used oncology drugs. We have identified ErbB3 inhibitors based on a novel biologic scaffold termed a surrobody. Two of these inhibitors appear to work by a previously unrecognized mechanism of action. As a consequence, they not only inhibited cell proliferation and intracellular signaling driven by stimulation with the ErbB3 ligand neuregulin (NRG), but also inhibited signaling and proliferation that was driven by overexpression of ErbB2 in the absence of ligand stimulation. In addition, the surrobodies inhibited tumor growth in vivo in both ErbB2-overexpressing and nonoverexpressing cells. In ErbB2-overexpressing cells, both of the anti-ErbB3 surrobodies significantly augmented the activities of trastuzumab, lapatinib, and GDC-0941, agents that inhibit cell proliferation by different mechanisms. Moreover, although NRG diminished the efficacy of these agents, when they were combined with anti-ErbB3 surrobodies the affect of NRG was abrogated. In this capacity, the anti-ErbB3 surrobodies were more effective than the ErbB2/ErbB3 dimerization inhibitory antibody pertuzumab. Despite the fact that these surrobodies appear to engage ErbB3 differently than previously described anti-ErbB3 antibodies, they retain all of the beneficial characteristics of this class of agents, including the ability to augment drugs that inhibit EGF receptor. These anti-ErbB3 agents, therefore, show substantial promise for development as single agents or in combination with other ErbB-directed antibodies or small molecules and may provide for a broader range of therapeutic indications than previously described anti-ErbB3 antibodies. Mol Cancer Ther; 11(7); 1411–20. ©2012 AACR.