The potential usefulness of alpha-particle radioimmunotherapy in the treatment of osteosarcoma was studied in vitro by using the monoclonal antibody TP-3 and cells of three human osteosarcoma cell lines (OHS, SAOS and KPDX) differing in antigen expression. Cell survival curves were established after treatment with (a) 211At-TP-3 of different specific activities, (b) 211At-labeled bovine serum albumin (BSA), (c) free 211At and (d) external-beam X rays. The three osteosarcoma cell lines showed similar survival curves, whether treated with external-beam X rays, 211At-BSA or free 211At. The D0's were lower for free 211At than for 211At-BSA. The survival curves for 211At-TP-3 treatment, on the other hand, differed significantly among the cell lines, suggesting that sensitivity to 211At-TP-3 treatment was governed by cellular properties other than sensitivity to external-beam X rays. The cellular property most important for sensitivity to 211At-TP-3 treatment was the antigen expression. Cell inactivation after 211At-TP-3 treatment increased substantially with increasing specific activity of the 211At-TP-3. At high specific activities, the cytotoxic effect of 211At-TP-3 was significantly higher than that of 211At-BSA. In conclusion, 211At-TP-3 has the potential to give clinically favorable therapeutic ratios in the treatment of osteosarcoma.