Interleukin 21 (IL-21) is a recently identified novel cytokine that plays an important role in the regulation of B, T, and NK cell functions. Its effects depend on binding to and signaling through an IL-21 receptor complex consisting of the IL-21 receptor (IL-21R) and the common γ-chain (γ c ). In this study using biosensor technique, the ligand-binding properties of IL-21R and γ c , which are presently poorly understood on a molecular level, were analyzed employing recombinant ectodomains of IL-21R and γ c . The formation of a binary complex between IL-21 and immobilized IL-21R (K D 70pM), γ c and immobilized IL-21 (K D 160μM) and a ternary complex between γ c and IL-21 saturated immobilized IL-21R (K D 160nM) could be analyzed. The γ c residues involved in IL-21 binding were defined by alanine-scanning mutational analysis. The epitope comprises γ c residues N44, Y103, N128, L161, E162, and L208. It is not identical but partially overlapping with the previously established γ c epitope for IL-4 binding. These results open the way to understand the molecular recognition mechanism in the IL-21 receptor system and also the promiscuous binding properties of γ c .