Active immunotherapy with tumor cells treated in vitro with Vibrio cholerae neuraminidase (VCN) plus mitomycin C augments the antitumor effects of local x irradiation in the treatment of firmly established methylcholanthrene-induced fibrosarcoma, MC-43, in syngeneic C3H/HeJ female mice. In most experiments, the inhibition of tumor growth was greater when VCN-treated tumor cells were combined with local irradiation than could be achieved with VCN-treated tumor cells or local irradiation alone. Even in those experiments in which the immunotherapeutic effect of VCN-treated cells was negligible, the combination of radiotherapy and immunotherapy appeared to be greater than irradiation alone. Similarly, total permanent regression of established tumors occurred more frequently after combined therapy than after immunotherapy or radiation therapy alone.