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Internal radiation therapy using intrahepatic arterial injection of <sup>90</sup>Y-labeled glass microspheres (<sup>90</sup>Y-microspheres) has proven to be a promising therapeutic modality for inoperative liver tumor. Recently, direct intratumoral injection of <sup>90</sup>Y-microspheres has been performed with even more encouraging results. The purpose of this study was to compare the treatment efficacy of these 2 methods using <sup>90</sup>Y-microspheres. <b>Methods:</b> Forty-eight male rats, each bearing a hepatic tumor, were divided into 4 groups (12 rats in each group) to evaluate the efficacy of treatment. Group 1 received an intratumoral injection of 37 MBq (1 mCi) <sup>90</sup>Y-microspheres. Group 2 received an intratumoral injection of 0.1 mL normal saline as the control group. Group 3 received an intra-arterial injection of 37 MBq (1 mCi) <sup>90</sup>Y-microspheres. Group 4 received an intra-arterial injection of 0.1 mL normal saline as the control group. Tumor size was measured by liver sonography before injection as well as at 2 and 4 wk after injection. Survival time was calculated from the day of treatment to 2 mo after treatment by Kaplan-Meier survival analysis. The response rate was evaluated by the change in tumor size and survival time. Fisher9s exact, 2-tailed test was used to compare response rates. <b>Results:</b> In the rats treated by intratumoral injection of <sup>90</sup>Y-microspheres, 83.3% (10/12) showed a good response. In contrast, all 12 rats in the control group showed a poor response. The difference was significant (<i>P</i> < 0.00001). Eighty-three percent (10/12) of the rats survived >60 d after intratumoral injection of <sup>90</sup>Y-microspheres, whereas only 25% (3/12) of the control rats survived >60 d. The difference was significant (<i>P</i> = 0.0068). In the rats treated by intra-arterial injection of <sup>90</sup>Y-microspheres, 58.3% (7/12) showed a good response to the treatment. All rats in the control group showed a poor response. The difference was significant (<i>P</i> = 0.0023). Sixty-six percent (8/12) of the rats survived >60 d after intra-arterial injection of <sup>90</sup>Y-microspheres, whereas only 16.7% (2/12) of the control rats survived >60 d. The difference was significant (<i>P</i> = 0.0385). However, the response rate and survival time between the intratumoral treatment group and the intra-arterial treatment group showed no significant difference (<i>P</i> = 0.3707 and 0.3988, respectively). <b>Conclusion:</b> Both methods (intratumoral treatment and intra-arterial treatment) showed a significantly good response rate and prolonged survival time compared with those of the control groups. However, no significant difference was found in the response rate or survival time between intratumoral treatment and intra-arterial treatment.