A comparative histopathologic study was performed on inbred guinea pigs at the site of a transplanted syngeneic hepatocarcinoma and in the draining lymph nodes, in the presence and absence of Mycobacterium bovis strain bacillus Calmette-Guérin (BCG). BCG was injected into the growing intradermal tumor 7 days after transplantation, which at that time had metastasized to the first regional lymph node. The histopathology was compared to that of saline-inoculated tumors and to that of animals in which tumors had been excised 7 days after transplantation. In this system guinea pigs die, because of metastases to vital organs, 60–90 days after intradermal injection of 106 hepatocarcinoma cells without BCG treatment. The results demonstrate that intradermal tumors completely regress after treatment with BCG and that regional lymph node metastases are eliminated. The mechanism is a BCG-mediated granulomatous reaction at both the tumor site and the regional lymph node. Histiocytes appear to be the major effector cells in the reaction. In this syngeneic tumor system, conventional lymphoproliferative response of the regional node, in the absence of histiocytosis, is insufficient to inhibit tumor growth.