Sarcoidosis is a chronic granulomatous disorder of unknown cause, characterized by activation of T-lymphocytes and macrophages. A Case Control Etiologic Study of Sarcoidosis (ACCESS) is a multicenter study designed to determine the etiology of sarcoidosis. The study organization includes 10 Clinical Centers, a Clinical Coordinating Center, specialized Core Laboratories, a Central Specimen Repository, and a Project Office at the National Heart, Lung, and Blood Institute. In addition to etiology, ACCESS will examine the socioeconomic status and clinical course of patients with sarcoidosis. We propose to enroll 720 newly diagnosed cases of sarcoidosis and compare them to 720 age, sex, and race matched controls and follow the first 240 cases for two years.Leads to the etiology of sarcoidosis have come from diverse sources: in clinical laboratory investigations, alveolitis has been found to precede granulomatous inflammation; in case control studies, familial aggregation has been identified; and in case reports, recurrence of granulomatous inflammation has been observed after lung transplantation. We describe the rationale for the study design based on genetic, environmental, infectious, and immune dysregulation hypotheses and the methods used for selecting controls.The cause may not prove to be a single, known exposure. Interactions of exposures with genetic predispositions would have important implications for our understanding of immune responses as well as the pathogenesis of sarcoidosis. Copyright (C) 1999 Elsevier Science Inc.