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Background: This study aimed to determine the impact of co-infection of Clonorchis sinensis (CS) and hepatitis B virus (HBV) on the prognosis of patients with hepatocellular carcinoma (HCC) following hepatectomy. Methods: The clinicopathological information of 946 patients with HCC following hepatectomy was retrospectively analyzed. The patients were divided into four groups depending on whether they had CS infection and/or HBV infection: double-negative group (infected with neither CS nor HBV), simple CS group (infected with only CS), simple HBV group (infected with only HBV), and double-positive group (co-infected with CS and HBV). Kaplan-Meier curves were used to evaluate the overall survival (OS) and recurrence-free survival (RFS), while log-rank tests were used to compare survival rates. Further, Cox regression was used to perform both univariate and multivariate survival analyses to identify variables linked to the prognosis of HCC. Results: The median overall survival (OS) and recurrence-free survival (RFS) in the double-positive, simple CS, simple HBV, and double-negative groups were 27 months and 9 months, 20 months and 7 months, 44 months and 12 months, and 42 months and 17 months, respectively. The double-positive group's 1-year, 3-year, and 5-year OS and RFS rates were 79.2% and 46.9%, 62.6% and 28.4%, 47.8%, and 12.2%, respectively. The simple CS group's 1-year, 3-year, and 5-year OS and RFS rates were 86.3% and 41.5%, 56.5% and 27.7%, 50.2%, and 18.5%, respectively. The simple HBV group's 1-year, 3-year, and 5-year OS and RFS rates were 89.8% and 56.0%, 72.5% and 30.5%, 63.8%, and 19.9%, respectively. The double-negative group's 1-year, 3-year, and 5-year OS and RFS rates were 91.5% and 62.3%, 76.1% and 32.9%, 64.0%, and 22.4%, respectively. Further, according to a Cox multivariate analysis, tumor size (> 5cm), Edmonson grade (III-IV), BCLC-C stage, and tumor satellite focus were independent risk factors for RFS and OS in patients with HCC. Conclusion: Patients with HCC and Clonorchis sinensis infection experience a poor prognosis after hepatectomy, regardless of whether they are co-infected with HBV. Author summary: Clonorchis sinensis inhabits the bile ducts of mammals, and clonorchiasis is a major public health concern in numerous countries. Infection with Clonorchis sinensis is a risk factor for cholangiocarcinoma. It is unknown whether it changes the prognosis of hepatocellular carcinoma patients or contributes to this disease's development. The hepatitis B virus is the leading cause of hepatocellular carcinoma. In addition, hepatitis B infection is prevalent in many endemic places for clonorchiasis, although the potential interaction between the two diseases has gotten little attention. This study aimed to determine the prognostic significance of Clonorchis sinensis infection and Clonorchis sinensis combined with HBV infection in patients with hepatocellular carcinoma after hepatectomy. Our results indicate that patients with hepatocellular carcinoma combined with Clonorchis sinensis infection have a worse prognosis after hepatectomy with or without HBV infection, providing evidence for future studies on the adverse effects of the interaction between the two on patients with hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]