Intermediate-stage hepatocellular carcinoma (HCC) targeted for transcatheter arterial chemoembolization (TACE) corresponds to a highly heterogeneous population for whom the factors predicting TACE efficacy have not been established. This study aimed to evaluate the impact of hypovascular hepatic nodules coexisting with intermediate-stage HCC as a significant predictive factor for TACE refractoriness. A total of 66 patients with intermediate-stage HCC who received initial TACE were retrospectively analyzed. Hypovascular hepatic nodules were detected by dynamic computed tomography or magnetic resonance imaging, as well as angiography, before all initial TACE. The time to TACE refractoriness (TTTR) was defined as the period from initial TACE until the diagnosis of TACE refractoriness. Hypovascular hepatic nodules were detected in 36 patients (54.5%), 15 (41.7%) of whom had a single nodule, whereas 21 (58.3%) had multiple nodules, and the median size of the maximum nodule was 10 mm (range 5-80 mm). The median TTTR was 17.4 months for all patients, and 7.3 and 33.1 months for patients with and without hypovascular hepatic nodules, respectively. The TTTR was significantly shorter for patients with hypovascular hepatic nodules than that for the other patients. In the multivariate analysis, the presence of hypovascular hepatic nodules (HR 7.016, 95% CI 3.534-13.930; P < 0.001) and being out of the up-to-seven criteria (HR 2.861, 95% CI 1.493-5.486; P = 0.002) were independent risk factors for a short TTTR. The presence of hypovascular hepatic nodules with intermediate-stage HCC represents a significant predictive risk factor for TACE refractoriness. © 2019 The Japan Society of Hepatology.