Purpose: We investigated the role of intraoperative iodine-125 (I-125) brachytherapy as a treatment option for unresectable primary and metastatic liver tumors. Methods and Materials: Between 1989 and 2002, 64 patients with unresectable or residual disease after surgical resection for intrahepatic malignancies underwent 160-Gy permanent I-125 brachytherapy. Results: The median length of follow-up was 13.2 years. The overall 1-year, 3-year, and 5-year actuarial intrahepatic local control rates were 44%, 22%, and 22%, respectively, with a median time to liver recurrence of 9 months (95% CI, 6-12 months). The 5-year actuarial intrahepatic control was higher for patients with solitary metastasis (38%) than for those with multiple metastases (6%, p = 0.04). The 1-year, 3-year, and 5-year actuarial overall survival rates were 73%, 23%, and 5%, respectively (median, 20 months; 95% CI, 16-24; longest survival, 7.5 years). Overall survival was higher for patients with smaller-volume implants (p = 0.003) and for patients without prior liver resection (p = 0.002). No mortality occurred. Radiation-related complications were minimal. Conclusions: For select patients with unresectable primary and metastatic liver tumors for whom curative surgical resection is not an option, I-125 brachytherapy is a safe and effective alternative to other locally ablative techniques and can provide long-term local control and increased survival. (C) 2006 Elsevier Inc.