Lack of tumor specificity renders current modalities for treating malignant glioma ineffective. The administration of 131I-labeled monoclonal antibody (Mab) 81C6, which reacts with the glioma-associated extracellular matrix antigen, tenascin, to nude mice carrying s.c. human glioma xenografts has resulted in significant tumor growth delay and tumor regression. In this study, we evaluated the therapeutic efficacy of 131I-labeled 81C6 in athymic rats bearing intracranial human glioma xenografts, a more appropriate model for human gliomas. Mab 81C6, an IgG2b immunoglobulin, and an isotype-matched control Mab, 45.6, were labeled at 12.5-23.6 mCi/mg with chloramine-T. The Mabs were given i.v. at 1.25 and 2.5 mCi/animal for 131I-labeled 81C6, and 1.25 mCi for 131I-labeled 45.6 control. Therapeutic response was evaluated by survival prolongation using Wilcoxon rank sum analysis. Three experiments were done. No significant survival prolongation was found in the trial in which the average tumor size at the time of Mab administration was 60 +/- 14 mm3, two-thirds the size which causes animal death. In experiment 2, Mab was given at 16 +/- 14 mm3 average intracranial tumor volume. Statistically significant (P less than or equal to 0.005) survival prolongation was found for animals treated with 2.5 mCi 131I-labeled 81C6. In that experiment, male animals with intracranial xenografts had significantly shorter survival than females (P less than or equal to 0.005). When only female animals were used in the analysis, the 1.25-mCi 81C6 group also was found to have longer survival benefit (P less than or equal to 0.01). In the third experiment, only female animals were used and the tumor size at the initiation of treatment was 20 +/- 9 mm3. Highly significant survival prolongation again was found in both 1.25 (P = 0.001) and 2.5 mCi (P less than 0.001) 131I-labeled 81C6 groups. The estimated dose to intracranial tumors from 1.25 mCi of 131I-labeled Mab was 1585 rads for 81C6 and 168 rads for 45.6. Dose to other organs from 81C6 and 45.6 was similar, ranging between 31 rads to the brain and 734 rads to the bone marrow. However, normocellularity was observed in most marrow tissue examined microscopically. Three animals receiving the low dose (1.25 mCi 81C6) survived for more than 71 days with apparent cures. In conclusion, intracranial human glioma xenografts were treated successfully with 131I-labeled 81C6 but not control Mab.