The presence of microvascular invasion (MVI) significantly impairs postoperative long-term survival of patients with hepatocellular carcinoma (HCC). The role of neoadjuvant radiotherapy (RT) in treating patients with an early-stage HCC predicted to have high risks of MVI remains to be explored. Consecutive patients with a resectable single and small (<= 5cm) Hepatitis B Virus (HBV)-related HCC predicted to have high risks of MVI were randomized 1:1 to receive either neoadjuvant intensity modulated radiation therapy (18Gy with fractionated doses of 3Gy) followed by surgery 4 weeks later or upfront surgery. The primary endpoint was disease-free survival (DFS). The secondary outcomes included overall survival (OS), objective response rate, RT-related toxicity and surgical complications. There were 30 patients randomized to each of the 2 groups. In the neoadjuvant RT group, 3 patients violated the study protocol, with 2 having upfront hepatectomy and 1 radiofrequency ablation after RT. The objective response rate after RT was 25.0% (7/28), but 2 patients suffered from grade 3 liver toxicity. The median follow-up was 68 months (interquartile range, 58-70mo) in the neoadjuvant RT group, and 68 months (interquartile range, 62-75mo) in the upfront surgery group. On intention-to-treat analysis, the median DFS and median OS were not reached in both the 2 arms. The 1-, 2-, 3- and 5-year DFS rates for the neoadjuvant RT group were 86.7%, 76.7%, 60.0% and 56.3%, versus 90.0%, 66.7%, 52.8% and 45.7% in the upfront surgery group (P = 0.448), respectively. The corresponding OS rates were 96.7%, 86.7%, 83.3% and 72.7%, versus 100.0%, 93.3%, 79.6% and 60.7% (P = 0.399). For patients with a resectable single and small HBV-related HCC predicted to have high risks of MVI, neoadjuvant RT gave a promising response rate with a mild toxicity. Nevertheless, the neoadjuvant RT yielded similar long-term DFS and OS rates compared to patients who underwent upfront surgery.