The huge demand for the most promising biopharmaceuticals, monoclonal antibodies (mAb), has resulted in a need for more efficient and less costly downstream purification processes for mAb. The currently used Protein A Agarose is unattractive due to toxic ligand leakage and high cost. In this study, three novel small peptide ligands, DWHW, CEWW and HEYW, were designed based on the interactions with human immunoglobulin G (IgG) using molecular simulations. The effects of pH, ionic strength and flow rate on the binding capacities to IgG were investigated. The static and dynamic binding capacities were determined. The dissociation constant (K-d) of the DWHW resin was 1.1 x 10(-5) M. The binding capacity of the DWHW resin was 24.5 mg ml(-1), which is comparable to Protein A Agarose. The DWHW resin was able to purify IgG from cMEM and CHO cell culture supernatants with a purity of more than 95% under elution conditions of pH 9 (50 mM sodium borate buffer) and pH 3 (50 mM glycine-HCl buffer). The results indicate that the small peptide ligands, especially DWHW, can offer a potential alternative for mAb purification.