This study aimed to retrospectively assess the outcome of interstitial iodine-125 brachytherapy for unresectable hepatocellular carcinoma (HCC).Between February 2013 and March 2019, 57 patients with 108 unresectable HCC lesions treated with computed tomography (CT)-guided iodine-125 seed brachytherapy were retrospectively analyzed. The primary endpoint was overall survival (OS). The secondary endpoints included local tumor control and progression-free survival (PFS). Potential factors associated with OS were assessed.The mean follow-up duration was 24.3 ± 15.6 months (median, 20.5 months; range, 3.9-66.8 months). The median OS time was 23.6 months (95% confidence interval [CI], 18.4-28.8 months). The 1-, 2-, and 3-year actuarial OS rates were 80.0%, 46.1%, and 24.3%, respectively. The median PFS time was 12 months (95% CI, 9.9-14.5 months). The 1- and 2-year actuarial PFS rates were 50% and 20.1%, respectively. Local progression was noted in 11 (11.3%) of 108 lesions with mean local control time of 20.5 ± 8.8 months. The 1- and 2-year local control rates were 96.5% and 88.8%, respectively. Barcelona clinic liver cancer stage and Child-Pugh score were independent risk factors affecting the prognosis (hazard ratio [HR] = 0.330 [95% CI, 0.128-0.853] and HR = 0.303 [95% CI, 0.151-0.610], respectively). Hepatic artery pseudoaneurysm was found in 1 (1.8%) patient with lesion located in the porta hepatis. No other major complications developed during follow-up.CT-guided iodine-125 brachytherapy may be an effective and safe alternative with promising survival and increased local control rate in unresectable HCC treatment.