Intratumor injection of OK-432, a biological response modifier, in the treatment of small HCC was studied in 7 inoperable patients. After evaluation with ultrasound (US), computed tomography (CT), angiography and US-guided biopsy, implantation of a steel coil in the tumor, intratumor injection was performed under US guidance. After completion of the treatment, liver biopsy and image studies were again done to evaluate the extent of tumor necrosis. One patient was alive and well without recurrence 19 months after treatment. Four had recurrent tumors at different site of the liver 4 months, 9 months, 9 months and 8 months later. Two died of progressive malignancy 3 months and 8 months later. In the 6 patients with elevated serum alpha-fetoprotein (AFP) levels, 4 had decreased AFP after treatment, and the 2 mortalities had steadily increased AFP. The most common side effects are fever and chills. Transient abdominal pain with elevated transaminase activities, cough with hemoptysis, and vomiting were seen in 1 case each. After treatment, the biopsy specimens showed total necrosis of HCC. Although the T4/T8 ratio of peripheral blood was increased as compared with that before treatment in 4 cases, peritumoral cytotoxic T lymphocyte and monocyte infiltration were seen in one specimen only, and another 7 examined specimens showed negative staining with monoclonal antibodies of T cells. We conclude that intratumor injection of OK-432 is an alternative treatment for small HCC in inoperable cases. The effectiveness may be due to the direct tumoricidal mechanism of OK-432.