Purpose To retrospectively evaluate whether thermal injury-induced hepatic parenchymal hypoperfusion can be a significant risk factor for tumor recurrence after radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC). Materials and Methods The institutional review board approved this retrospective study, and the requirement to obtain informed consent was waived. The study population comprised 130 patients (87 men, 43 women; mean age, 61.4 years ± 8.95; age range, 39-84 years) with single nodular HCCs smaller than 5 cm who underwent RFA between January 2011 and December 2012. The development of RFA-induced hepatic parenchymal hypoperfusion was assessed with follow-up computed tomography (CT). After a mean follow-up of 36.7 months ± 10.8, the authors analyzed the overall and recurrence-free survival and the cumulative incidence of each type of recurrence (ie, local tumor progression [LTP], intrahepatic distant recurrence [IDR], and extrahepatic metastasis) by evaluating prognostic factors with use of the Kaplan-Meier method and Cox proportional hazard regression model. Results RFA-induced hepatic parenchymal hypoperfusion developed in 41 of the 130 patients (31.5%) but did not have a significant effect on overall survival (P = .634). However, the estimated 3-year recurrence-free survival rate was 43.3% in the 41 patients with RFA-induced hepatic parenchymal hypoxia and 61.9% in the 89 patients without hypoxia, a statistically significant difference (P = .019). The 3-year cumulative incidence of IDR was significantly higher in patients with RFA-induced hepatic parenchymal hypoperfusion than in those without hypoxia (33.3% vs 54.1%, P = .006). Conversely, the 3-year cumulative incidence of LTP and extrahepatic metastases showed no significant differences (P > .05 for both). Conclusion The development of RFA-induced hepatic parenchymal hypoperfusion is a significant predictive factor of recurrence (of IDR in particular) after RFA of a single nodular HCC. RSNA, 2016 Online supplemental material is available for this article.