This study demonstrates an essential role for interleukin-4 (IL-4) in the delayed hypersensitivity reaction, as illustrated by contact sensitivity (CS) to trinitrochlorobenzene (TNCB). Injection of mice with monoclonal antibody to IL-4, but not with control antibody, reduced CS after active immunization by 75%, as judged by ear swelling. The histological alterations of CS were also reduced. IL-4 was essential to the effector stage, as inhibition of its production or action blocked the passive transfer of CS. In particular, treatment of immune lymph node cells with antisense oligonucleotide to IL-4 inhibited the systemic transfer of CS. Transfer was also inhibited by monoclonal antibody to IL-4 given to the recipient. The present results indicate that IL-4 is an essential cytokine at the effector stage of the CS reaction.