Studies of ceroid associated lesions in Hermansky-Pudlak syndrome (HPS) indicate that restrictive lung disease and granulomatous gastrointestinal lesions are ampng the most frequent and account for 60% of the deaths of the patients. No ultrastructural and chemical studies show accumulation of nonbiodegradable ceroid in tissue cells and associated macrophages of HPS patients. There is no known degradative pathway for ceroid. Ceroid is eliminated from cells by exocytosis. Wild type and pale eared mice treated with leupeptin, which inhibits exocytosis, accumulate ceroid in organ cells in the same sequence seen in HPS. Young HPS patients without significant pulmonary function deficits were lavaged, the macrophages examined by TEM and tested for platelet derived growth factor. Macrophages contained ceroid and 7/12 patients had 27 ± 42 units of PDGF bioactivity compared to zero activity in controls. Purified ceroid was fed to macrophages lavaged from the lungs of non-smoking control subjects. Prior to feeding, less than 5% of cells contained one or two small yellow-orange autofluorescent granules resembling ceroid. After feeding, approximately 20% of control cells had ingested ceroid, but dies and the production of PDGF by macrophages which precedes lung fibrosis all point to a central role of the macrophage in these lesions. These studies did not distinguish whether the macrophages ingested ceroid from other cells, or whether ceroid is produced intrinsically by the HPS macrophage.