Background: The previous results of our trial demonstrated that the addition of induction chemotherapy (IC) prior to definitive chemoradiotherapy (CRT) failed to significantly improve response rate or 3-year survival in patients with locally advanced esophageal squamous cell carcinoma (ESCC). Here, we report the long-term results and exploratory analyses to further evaluate the therapeutic value of IC in ESCC. Methods: This was a single-institution, open-label, randomized, phase II trial. Patients with previously untreated, unresectable, stage II–IVA ESCC were randomly assigned in a 1:1 ratio to receive induction docetaxel (75 mg/m² on day 1) and cisplatin (75 mg/m² on day 1) every 3 weeks for two cycles, followed by concurrent CRT, or CRT alone. The primary endpoint was overall response rate at 3 months after CRT. Second endpoints were overall survival (OS) and progression-free survival (PFS). The relationship between tumor response to IC and long-term survival was analyzed as an exploratory, post-hoc analysis. Moreover, baseline tumor biopsies were evaluated by RNA-seq to identify patients who are more likely to benefit from IC. Results: Between May 2015 and September 2017, 110 eligible patients were randomly assigned to the IC+CRT group (n=55) or the CRT group (n=55). The overall response rate was 74.5% in the IC+CRT group versus 61.8% in the CRT group (P=0.15). At a median follow-up of 74.9 months, the 5-year OS rate was 31.8% in the IC+CRT group and 29.1% in the CRT group (P=0.68; HR, 0.91; 95% CI, 0.58–1.43). Similarly, no significant differences were identified in 5-year PFS between groups (30.5% vs. 25.5%, P=0.51; HR, 0.86; 95% CI, 0.56 to 1.34). Patients who responded to IC had significantly better survival than nonresponders. Six key genes were identified based on RNA-seq and gene expression comparison between responders and nonresponders after IC. Risk-score model was constructed by these key genes and then validated. Conclusions: Addition of induction docetaxel plus cisplatin before definitive CRT still failed to provide an obvious survival benefit in ESCC based on long-term follow-up. However, this strategy did result in a significantly improved survival in IC responders. Our results also revealed potential molecular biomarkers to predict who may benefit from IC. Clinical trial information: NCT02403531.