Objective To explore the effect of nutritional therapy on the clinical efficacy and immune response of patients with unresectable locally advanced esophageal squamous cell carcinoma undergoing radiotherapy and chemotherapy. Methods A total of 100 patients with locally advanced esophageal squamous cell carcinoma from May 2018 to may 2019 in Rugao Hospital Affiliated to Nantong University were enrolled. They were treated with 5-fluorouracil and cisplatin based chemotherapy and concurrent radiotherapy. They were divided into conventional treatment group (53 cases) and nutritional treatment group (47 cases), Objective to analyze the correlation between nutritional therapy and treatment response and immune status of patients. Results Nutritional therapy group in the incidence of neutropenia, objective response rate, the change of serum albumin and length of hospital stay were significantly better than routine nursing group. In addition, IgG and IL ⁃2 levels from the nutrition therapy group were obviously higher than those of routine nursing group, natural killer, higher percentage of CD3+and CD4+T cells, CD4+/CD8+ T cell ratio were higher (P<0.05). Nutrition therapy group patients significantly lowered level of IL⁃6. Conclusion Nutrition care plan can improve treatment compliance, reduce the radiation and chemotherapy in patients with LAOSCC toxicity and length of hospital stay, enhance the immune response.