Background: Hyperthermic intraperitoneal chemotherapy (HIPEC) is the main treatment for peritoneal carcinomatosis (PC).However, It is still a major problem to predict the efficacy of HIPEC. Some studies have shown that peritoneal cancer index (PCI) can be used to predict the efficacy of HIPEC, but the invasiveness and inaccuracy are shortcomings. Therefore, we need a minimally invasive and accurate prediction biomarker. Many studies have confirmed that circulating tumor DNA (ctDNA) can accurately predict the efficacy and prognosis of various solid tumors. This study aimed to evaluate the predictive value of ctDNA from ascites and plasma for HIPEC. Methods: Eligible PC patients should be defintive diagnosed by pathology or cytology. Each patient was treated with HIPEC for 4 times, with an interval of 3 days each time. Plasma and ascites samples were collected before HIPEC and after the last HIPEC. All samples were detected by next generation sequencing (NGS). The molecular tumor burden index (mTBI) and main clone variant allele fraction (VAF) changes were used as the prediction indexes of efficacy. In addition, The changes of common tumor markers such as CEA during the same period were used as controls. Results: A total of 19 patients with PC were enrolled from November 2018 to January 2020. Firstly, the mTBI changes of 14 patients whom had plasma samples at two time points (baseline and postHIPEC)were analyzed. Among them, 3 patients had no gene mutation were detected in two time points. There were significant differences in mTBI before and after HIPEC in the remaining 11 patients (Wilcoxon， p = 0.026). the median Ascites progression free survival (PFS) was 3.35 months (95% CI: 2.34 – 5.13 months), and the median overall survival (OS) was 5.93 months (95% CI: 4.93 – 11.17 months). The mTBI decline was significantly positively correlated with ascites PFS (Spearman r = 0.673, p = 0.023) and moderately positively correlated with OS (Spearman r = 0.510, p = 0.109). The highest VAF in plasma samples was defined as the main clone mutation. The main clone VAF decline was moderately positively correlated with ascites PFS (Spearman r = 0.588, p = 0.057) and slightly positively correlated with OS (Spearman r = 0.386, p = 0.241). As the controls, We found that the common tumor markers decline was no correlated with ascites PFS(Spearman r = 0.091, p = 0.790) and OS (Spearman r = 0.287, p = 0.396). We further analyzed the correlation of VAF between ascites and plasma co-mutation genes in 12 patients. The VAF of co-mutated genes in plasma and ascites was positively correlated (Spearman r = 0.794, p = 0.001). Conclusions: Plasma ctDNA can be used as a biomarker for predicting the efficacy of HIPEC for peritoneal carcinomatosis, and its accuracy is significantly higher than comon tumor markers. However, a larger sample size study are needed to validate our results.