The combination of toripalimab (an anti-PD-1 antibody) with definitive chemoradiotherapy (CRT) demonstrated encouraging efficacy against locally advanced esophageal squamous cell carcinoma (ESCC) in the EC-CRT-001 phase II trial. This exploratory analysis evaluated the role of circulating tumor DNA (ctDNA) and blood-based tumor mutational burden (bTMB) in predicting the response and survival. We found that ctDNA-negative patients achieved a higher clinical complete response rate (cCR) compared to those with detectable ctDNA during CRT (83%, 19/23 vs. 39%, 7/18; p=0.008) or post-CRT (78%, 21/27 vs. 30%, 3/10; p=0.017). Patients with detectable ctDNA during CRT had shorter progression-free survival (PFS) (p=0.014). Similarly, patients with post-CRT detectable ctDNA had a significantly shorter PFS (p=0.012) and worse overall survival (OS) (p=0.004). Moreover, patients with high bTMB levels during CRT had prolonged OS (p=0.027). In conclusion, ctDNA and bTMB has the potential for predicting treatment efficacy and survival in ESCC treated with CRT and immunotherapy.