Purpose To evaluate incidence and predictive factors for the vascular lake phenomenon (VLP), as well as to compare local and overall tumor response in patients with and without VLP induced during DEB-TACE for HCC. Methods A total of 200 consecutive patients with 323 HCC nodules underwent first-session DEB-TACE from 2011 to 2014. Patients were divided in two groups, according to the presence of the VLP during DEB-TACE. Pre- and post-treatment imaging studies (CT or MRI) were performed. Primary endpoint was assessment of tumor response, evaluated by mRECIST. Comparison of response rates between the VLP group and the non-VLP group was performed. Secondary endpoints were the determination of incidence rate and predictive factors for the VLP. Results The VLP was observed in 39/323 (12.1%) of the nodules treated. At multivariate logistic regression analysis, tumor size ≥3 cm in diameter (OR 13.95; 95% CI 3.60–54.05), presence of a pseudocapsule (OR 6.67; 95% CI 1.45–30.59) and alpha-fetoprotein levels (OR 1.004; 95% CI 1.000–1.007) remained predictive for the VLP occurrence. On a nodule-based analysis ( p  < 0.001), target lesion response analysis ( p  = 0.003) and overall response analysis ( p  = 0.004) the VLP group presented a higher objective response rate than the non-VLP group. Conclusion VLP is observed in 12% of the patients and happens more frequently in large and encapsulated tumors. It seems to be associated with better local and overall responses in HCC patients who underwent DEB-TACE.