We encountered 16 patients with connective tissue disease in whom pulmonary fibrosis developed. Routine light microscopic, ultrastructural, and direct immunofluorescent analyses were conducted, and circulating antibodies, including those of endothelial cell derivation, were assessed using indirect immuno-fluorescence and Western blot assays. Underlying diseases were dermatomyositis, scleroderma, mixed connective tissue disease, sclerodermatomyositis, Sjögren syndrome, rheumatoid arthritis, and anti-Ro-associated systemic lupus erythematosus. Antibodies to one or more Ro, RNP, Jo 1, OJ, and/or nucleolar antigens were seen in all cases and antiphospholipid antibodies in half. All biopsies revealed microvascular injury in concert with intraparenchymal fibrosis; in some cases, there were corroborative ultrastructural findings of microvascular injury. Patterns of fibroplasia represented nonspecific interstitial pneumonitis and usual interstitial pneumonitis. We noted IgG, IgA, and/or complement in the septal microvasculature. In 6 cases with available serum samples, indirect immunofluorescent endothelial cell antibody studies were positive and Western Blot studies showed reactivity of serum samples to numerous endothelial cell lysate-derived proteins. Pulmonary fibrosis, a recognized complication of systemic connective tissue disease, develops in connective tissue disease syndromes with pathogenetically established immune-based microvascular injury at other sites. A similar mechanism of antibody-mediated endothelial cell injury may be the basis of the tissue injury and fibrosing reparative response.