Downregulation of the epidermal growth factor receptor family of receptors is improved by combining different antibodies to noncompetitive epitopes. For ErbB2/HER2 this has already been translated into clinical practice by using a combination of trastuzumab and pertuzumab. Moreover, cocktails of 2 or 3 anti-epidermal growth factor receptor antibodies show an enhanced downregulation of the receptor due to the induction of matrix formation. A more efficient method for inducing matrix formation and receptor downregulation might include the use of trispecific reagents. A triparatopic Tribody consisting of 3 noncompeting ErbB2 binders was compared with equivalent trivalent monoparatopic counterparts, as well as to a cocktail of 3 monoclonal antibodies for its effects on downregulation of the ErbB2 receptor’s kinase activity and survival of several ErbB2-expressing cancer cell lines. The triparatopic Tribody was significantly more efficient in downregulating ErbB2 and inhibiting tumor cell growth than either the control monoparatope tribodies or the combinatorial treatment with the 3 different parental antibodies on all the tested tumor cells, including trastuzumab-resistant cell lines. The enhancement of effectivity was dependent on all 3 binding moieties. Because the novel Tribody allows reduction of the costs of production (as only 1 construct provides the antitumor effects of 3 antibodies) and has an intermediate molecular size (∼100 kDa) well suited for both tumor penetration and acceptable half-life, it has the potential to become a precious tool for therapeutic use particularly in trastuzumab-resistant cancer patients.