In this study, 'ABA'-type triblock copolymers of vitamin E-functionalized polycarbonate and poly(ethylene glycol), i.e., VitEm-PEG-VitE m, with extremely short hydrophobic block VitEm, are synthesized and employed to form physically cross-linked injectable hydrogels for local and sustained delivery of Herceptin. The hydrogels are formed at low concentrations (4-8 wt%). By varying polymer composition and concentration, the rheological behavior, porosity, and drug release properties of hydrogels are readily tunable. The in vitro antitumor specificity and efficacy of Herceptin in hydrogel and solution are investigated by MTT assay against normal and human breast cancer cell lines with different HER2 expression levels. The results demonstrate that the Herceptin-loaded hydrogel is specific towards HER2-overexpressing cancer cells and cytotoxic action is comparable to that of the Herceptin solution. The biocompatibility and biodegradability of hydrogel are evaluated in mice with subcutaneous injection by histological examination. It is observed that the hydrogel does not evoke a chronic inflammatory response and degrades within 6 weeks post administration. Biodistribution and anti-tumor efficacy studies performed in BT474 tumor-bearing mice show that single subcutaneous injection of Herceptin-loaded hydrogel at a site close to the tumor enhances the retention of the antibody within the tumor. This leads to superior anti-tumor efficacy as compared to intravenous (i.v.) and subcutaneous (s.c.) delivery of Herceptin in solution. The tumor size shrank by 77% at Day 28. When the hydrogel is injected at a distal location away from the tumor site, anti-tumor efficacy is similar to that of weekly i.v. injections of Herceptin solution over 4 weeks, with the number of injections reduced from 4 to 1. These findings suggest that this hydrogel has great potential for use in subcutaneous and sustained delivery of antibodies to increase therapeutic efficacy and/or improve patient compliance. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.