A model for pulmonary interstitial fibrosis (PIF) based on cell-mediated immune response is described. Animals were primed for contact hypersensitivity responses by skin painting with trinitrophenol (TNP), but instead of challenging with the antigen on the skin, animals were challenged with a single intratracheally administered dose of the immunizing hapten. Primed animals developed inflammation followed by pulmonary fibrosis, as determined by histologic examination. Furthermore, immunized animals developed an increase in hydroxyproline (as an indirect measure of collagen synthesis) that could be recovered from the lung by 7 days after an intratracheal challenge with TNP. The increase in hydroxyproline within the lung persisted through 30 days. The response was specific because little or no fibrosis or increase in collagen deposition was observed in immune animals that were challenged with an unrelated hapten (dinitrophenol). Unimmunized animals demonstrated a slight increase in hydroxyproline in the lung 7 days after challenge, but with time the collagen content of these control animals approached normal levels. These studies demonstrate that a specific cell-mediated immune response to a hapten within the lung can induce pulmonary interstitial fibrosis.