The clinical significance of an erythrocyte sedimentation rate (ESR) elevation of 100 mm or more in one hour was determined for 263 patients. Malignancy was diagnosed in 152 (58%) of these, and was associated with metastasis in all but two instances. Inflammatory diseases (infection or collagen disease) accounted for the elevation in 66 (25%) of the patients, whereas renal disease was the cause in 22 (8%). For only 17 (6%) of the patients was the diagnosis initially indeterminate or not related to the degree of ESR elevation. A serious disease was subsequently diagnosed in only three of these 17 patients. The diagnosis was not apparent from the history, physical examination, and basic laboratory tests of 12 patients. Tests that ultimately led to the diagnosis included the serum protein electrophoresis, bone marrow examination, roentgenograms of the abdomen or lumbar spinal column, and blood urea determinations.