T he universal features of the histopathology of fibrotic lung disease are derangement of parenchymal collagen and infiltration of the parenchyma with chronic inflammatory cells. To determine if this cellular reaction might be associated with autoimmunity to a consitituent of the alveolar interstitium, peripheral blood lymphocytes were exposed to human type I collagen in vitro and evaluated for the production of migration inhibition factor and cytotoxicity. Data from 18 patients with idiopathic pulmonary fibrosis, 8 patients with pulmonary fibrosis other than idiopathic pulmonary fibrosis, 12 patients with nonfibrotic lung disease, and 9 normals demonstrated that circulating lymphocytes from more than 94% of patients with fibrotic lung disease take part in processes where the recognition of collagen results in migration inhibition factor production and lysis of collagen-coated sheep red blood cells. These collagen-induced cell-mediated phenomena are obviated with human T-lymphocyte antiserum. Collagen-induced migration inhibition factor production and cytotoxicity were found in less than 20% of patients with nonfibrotic disease and were not found in normals. Qualitatively, there was no organ (lung, skin) or species (human, rabbit) collagen specificity in these assays, but human lung alpha 2 chains were recognized more often than alpha 1(I) chains. Circulating lymphocytes from patients with fibrotic disease are present in a normal T to B ratio. These lymphocytes did not incorporate [3H]thymidine when exposed to collagen but did when exposed to T-cell mitogens. These in vitro observations suggest that circulating T-lymphocytes and lung collagen may be intimately associated in the pathogenesis of human fibrotic lung disease.