We carried out a prospective study of the effectiveness of a diagnostic strategy in forty consecutively seen patients who had skeletal metastases of unknown origin. The diagnostic strategy consisted of the recording of a medical history; physical examination; routine laboratory analysis; plain radiography of the involved bone and the chest; whole-body technetium-99m-phosphonate bone scintigraphy; and computed tomography of the chest, abdomen, and pelvis. After this evaluation, a biopsy of the most accessible osseous lesion was done. The laboratory values were non-specific in all patients. The history and physical examination revealed the occult primary site of the malignant tumor in three patients (8 per cent): one patient who had carcinoma of the breast; one, of the kidney; and one, of the bladder. Plain radiographs of the chest established the diagnosis of carcinoma of the lung in seventeen patients (43 per cent). Computed tomography of the chest identified an additional six primary carcinomas of the lung (15 per cent). Computed tomography of the abdomen and pelvis established the diagnosis in five patients (13 per cent): three patients who had carcinoma of the kidney; one, carcinoma of the liver; and one, carcinoma of the colon. Examination of the biopsy tissue established the diagnosis in only three additional patients (8 per cent) and confirmed it in eleven others. On the basis of the biopsy alone, we were unable to identify the primary site of the malignant tumor in twenty-six (65 per cent) of the patients. In thirty-four (85 per cent) of the forty patients, the primary site was identified with the use of the diagnostic strategy described here, and only two additional occult malignant tumors were found on follow-up studies. Our diagnostic strategy was simple and highly successful for the identification of the site of an occult malignant tumor before biopsy in patients who had skeletal metastases of unknown origin.