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Purpose The survival benefits of patients with inoperable hepatocellular carcinoma (HCC) who undergo transarterial chemoembolization (TACE) and receive sorafenib therapy remain controversial. We aimed to identify clinical predictors in patients with inoperable HCC undergoing TACE and receiving sorafenib. Methods Between January 2014 and December 2017, 148 consecutive patients with inoperable HCC who were treated with TACE plus sorafenib were retrospectively analyzed. Critical clinical factors associated with overall survival (OS) were identified by Cox regression model analysis. Kaplan–Meier methods were used to calculate the survival times, which were compared with the log-rank test. Results Macrovascular invasion (MVI), radiologic response and sorafenib-related dermatologic toxicities were identified as independent factors associated with OS. MVI is a known prognostic factor before treatment. The median OS of patients with either radiologic response or dermatologic toxicities was significantly improved compared with that of patients without it (both 23.0 vs. 7.0 months, P < 0.001). The median OS of patients with a combination of radiologic response and dermatologic toxicities was significantly longer than that of patients with either radiologic response or dermatologic toxicities, as well as no response (25.0 vs. 14.0 vs. 6.0 months, respectively, P < 0.001), and the predictive value was confirmed across patients with different baseline characteristics in terms of MVI, α-fetoprotein level, performance status and liver function. Conclusion The combination of radiologic response and sorafenib-related dermatologic toxicities is the most robust predictor of survival benefits for HCC patients after TACE plus sorafenib therapy. Level of Evidence Level 3.