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. There is currently an urgent need for additional risk stratification for patients with PC to inform treatment decisions. The detection of circulating tumor DNA (ctDNA) represent a promising candidate liquid biopsy that may help to achieve this goal in a minimally invasive fashion. This study aimed to evaluate the predictive value of ctDNA from ascites and serial plasma for HIPEC. Methods: 19 patients with PC were enrolled. Plasma and ascites samples were collected before HIPEC and after the last HIPEC. Ascites and Serial plasma ctDNA were analyzed by next-generation sequencing (NGS). The molecular tumor burden index (mTBI) was used to detect ctDNA, and concurrent changes in the dominant clone variant allele frequency (VAF) and common tumor markers, were used as controls. The correlation between ascites and plasma ctDNA co-mutated genes was expressed by the VAF. Results: 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 (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 (r = 0.673, p = 0.023) and moderately positively correlated with OS (r = 0.510, p = 0.109). The highest VAF in plasma samples was defined as the main clone mutation. The dominant clone VAF decline was moderately positively correlated with ascites PFS (r = 0.588, p = 0.057) and slightly positively correlated with OS (r = 0.386, p = 0.241). As the controls, We found that the common tumor markers decline was no correlated with ascites PFS(r = 0.091, p = 0.790) and OS (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 (r = 0.794, p = 0.001). In addition, ascites PFS (P = 0.003, HR 0.157, 95%CI: 0.046–0.540) and OS (P = 0.017, HR 0.296, 95% CI: 0.109–0.804) in the low mTBI group (mTBI＜0.67) at baseline were significantly better than those in the high mTBI group (mTBI≥0.67). Conclusions: Serial Plasma ctDNA can be used as a biomarker for predicting the efficacy of HIPEC for PC, and its accuracy was significantly higher than that of the dominant clone VAF and concurrent tumor markers. A high baseline mTBI (≥0.67) may be an independent risk factor for prognosis. However, a larger sample size study are needed to validate our results. Clinical trial information: ChiCTR2000035025.