We have previously demonstrated that CD4 gene-targeted mutant mice (CD4− mice) demonstrate hyporesposiveness in contact hypersensitivity (CHS) suggesting that CD4 molecules are required for optimal induction of CHS. In the present study, we wished to examine the mechanisms of this hyporesponsiveness, in particular, we examined whether cytokines were altered in the skin and lymph nodes of CD4− mice following exposure to the contact allergen dinitrofluorobenzene (DNFB). Cytokine mRNA in the ear skin and draining lymph nodes (DLN) were examined by reverse transcription–polymerase chain reacion (RT–PCR) at various times after sensitization. Skin cytokine patterns revealed that in normal mice, interleukin (IL)-2, interferon (IFN)-γ and tumour necrosis factor (TNF)-α mRNA levels increased at 12 hr sensitization, whereas these cytokines were below the level of detection in CD4− mice. In the DLN of normal mice following the hapten application, sequential upregulation of cytokine mRNA including IL-1α, IL-1β, IL-2, IL-4, IL-10, IFN-γ and TNF-α was found. No change was seen for IL-1α, IL-1β, IL-10 and TNF-α and IL-2, IL-4 and IFN-γ mRNA levels were below the level of detection in DLN from CD4– mice following the hapten application. However, IL-1β, IL-2 and TNF-α mRNA levels of lymph node cells from CD4− mice could be upregulated by phorbol myristate acetate in vitro. Flow cytometry study has revealed that the number of Langerhans’ cells (LC) in DLN of CD4− mice was similar to that of normal mice, thus, inferring that the alterations of cytokine milieu in the ear skin did not have a significant effect on LC migration to DLN. These results suggest that CD4 molecules are crucial for the induction of certain cytokines in the skin and in inducing sequential cytokine signals in DLN required for optimal development of CHS, but that these changes in cytokines do not effect LC migration.