According to the effect of preoperative chemotherapy for tongue cancer, if the operation method is modified, the modality of treatment for tongue cancer will contribute to preserve the tongue in terms of function and aesthetics as well as improve the quality of life. A clinicopathologic study on 81 patients with tongue cancer was conducted to elucidate the relationship between clinical and histological effects of preoperative chemotherapy with a single agent and multiple-drug regimens, in order to determine the safe surgical margins in the resection of squamous cell carcinoma of the tongue. Fifty patients were treated with bleomycin alone, sixteen with bleomycin and methotrexate and another fifteen with bleomycin, OK-432 and cisplatin. Multiple-drug regimens resulted in greater response rates than the single agent, but there was not always agreement in the relationship between the tumor regression rate and the histological effects of chemotherapy. The histological effects, including the residual aspects of the tumor cell population, were associated with the grade of histological malignancy according to the mode of tumor cell invasion, mitotic index of tumor cell, the tumor differentiation, the degree of stromal lymphocyte infiltration and cellular atypism. These data indicate that special consideration should be also given to the degree of histological malignancy for biopsied specimen, in addition to the tumor regression rate, in determining safe surgical margins and in the modality of treatment of tongue cancer.