The crystal structure of recombinant human interleukin-4 (rhuIL-4) was initially determined at 3.5-Å resolution by multiple isomorphous replacement techniques and subsequently refined to a resolution of 2.35 Å by simulated annealing. The final crystallographic R-factor, based on all data in the range 6.0-2.35 Å (7470 reflections), is 0.232. Bond lengths and bond angles in the molecule have root mean square deviations from ideal values of 0.016 Å and 2.4°, respectively. The overall structure is highly compact and globular with a predominantly hydrophobic core. The main structural feature of rhuIL-4 is a four α-helix bundle, which composes approximately 58% of the structure. The helices are arranged in a left-handed antiparallel bundle with two overhand connections. Within these connections is a two-stranded antiparallel β-sheet. Both the tertiary and secondary structures of rhuIL-4 are similar to those of human granulocyte-macrophage colony-stimulating factor. Critical regions for receptor binding are proposed.