The crystal structure of interleukin-22 expressed in Drosophila melanogaster S2 cells (IL-22(Dm)) has been determined at 2.6 A resolution. IL-22(Dm) crystals contain six molecules in the asymmetric unit. Comparison of IL-22(Dm) and IL-22(Ec) (interleukin-22 produced in Escherichia coli) structures reveals that N-linked glycosylation causes only minor structural changes to the cytokine. However, 1-4 A main-chain differences are observed between the six IL-22(Dm) monomers at regions corresponding to the IL-22R1 and IL-10R2 binding sites. The structure of the carbohydrate and the conformational variation of IL22(Dm) provide new insights into IL-22 receptor recognition.