While recent evidence from several laboratories has shown that interleukin-4 (IL-4) can act on a number of cells in addition to B lymphocytes, these have thus far been limited to cells of the hematopoietic lineage. Here we report that murine IL-4 promotes DNA synthesis in both primary and immortalized fibroblasts. Marked stimulation of [3H]thymidine incorporation was observed for primary skin fibroblasts or Balb/c3T3 cells stimulated with HPLC- or immunoaffinity-purified as well as recombinant IL-4. Responses to immunoaffinity and recombinant IL-4 were completely blocked with anti-IL-4 antibody. Similar dose/response relationships were observed for recombinant IL-4 on skin fibroblasts and an IL-4 responsive murine T cell tumor, suggesting that the receptors for this lymphokine on these cells is similar. Together, these results show that IL-4 can cause DNA synthesis by murine fibroblasts presumably through ligand-receptor interactions at the cell surface. Implications of these findings to inflammation during an immune response is discussed.