We evaluated sequential thallium scans on both early images (EI) and delayed images (DI) for 62 patients who had bone and soft tissue lesions. The purpose was to determine whether this technique could be used to ascertain accurately whether lesions were malignant or benign and to predict the response to chemotherapy. The thallium-201 chloride (201Tl) accumulation in malignant tumors and benign lesions was statistically different. Sensitivity, specificity, and accuracy for 201Tl scans in detecting malignant tumors was 94%, 65%, and 82%, respectively, for EI, and 94%, 85%, and 90%, respectively, for DI. On multivariate analysis, significant independent factors for 201Tl uptake were malignant lesions on EI and DI and high cellularity on EI. Thirteen patients with malignant bone and soft tissue tumors underwent 201Tl scans before and after preoperative chemotherapy. There was a good correlation between percentage of tumor necrosis and percentage change of accumulation in lesion-to-normal tissue ration, and the correlation coefficient was higher on EI ( r = 0.801) than on DI ( r = 0.664). These results support the notion that 201Tl scintigraphy, although showing some false-positive and false-negative findings, is a useful tool in the evaluation of either malignant tumors or benign lesions. Furthermore, 201Tl scans on EI provide benefit concerning the evaluation of chemotherapeutic response in patients with malignant bone and soft tissue tumors.