Fibrosing alveolitis associated with systemic sclerosis (FASSc) is considered to be histologically and radiologically indistinguishable from lone cryptogenic fibrosing alveolitis (CFA). To date, the natural history of the two diseases has not been compared directly in large groups of patients followed at a single institution. We evaluated the survival of 205 patients with CFA and 68 patients with FASSc. Deaths during the follow-up period were reported in 142 patients with CFA (70%) and in 11 patients with FASSc (16%). Unadjusted survival from the onset of dyspnea was less in CFA than in FASSc (odds ratio, 3.3; p < 0.001); this difference persisted after adjustment for age of onset of dyspnea and smoking history. Survival from presentation was less in CFA (odds ratio approximately 3.3) after adjustment for age of presentation, smoking history, and initial pulmonary function indices. These differences persisted when analysis was confined to patients with histologic confirmation of fibrosing alveolitis and after adjustment for treatment. In patients undergoing computed tomography (CT) of the lungs, survival was less in CFA after adjustment for extent of abnormal lung on CT and CT pattern of disease (odds ratio, 3.9; p < 0.001). These findings indicate that despite their histologic and radiologic similarities, lone CFA and FASSc have different courses.