Abstract: Objective To systematically analyze the epidemiological profiles and cause-specific mortality patterns among hepatitis C death cases in Hongkou District, Shanghai and to provide a scientific basis for the rational planning of medical resources and targeted prevention and control of hepatitis C. Methods A retrospective cross-sectional study was conducted through integration of historical surveillance data from China Disease Prevention and Control Information System and Shanghai Municipal Death Medical Registration System. Data on demographic characteristics, hepatitis C clinical records and management records, and underlying causes of death among hepatitis C death cases from 2012 to 2024 in Hongkou District, Shanghai were collected. Descriptive statistical analysis was performed to analyze the epidemiological profiles and cause-specific mortality patterns of hepatitis C deaths. Group comparisons were conducted to analyze the distribution patterns of death cases and causes of death. Results The mean age at death among hepatitis C death cases was (69.49±12.75) years from 2012 to 2024 in Hongkou District, Shanghai. The majority were male and retired, accounting for 71.59% and 73.53% of cases, respectively. The leading three causes of death were malignant tumor (45.10%), cerebrovascular diseases (15.20%) and cardiovascular diseases (12.25%), collectively accounting for 72.55% of deaths. HCV-related deaths accounted for 9.80% of all deaths and the mean age at death was (63.41±11.81) years. The groups were defined based on gender, occupation, diagnostic criteria-based category, treatment status, presence of other liver diseases, and compliance. No statistically significant difference in HCV-related mortality was found between/among these groups(all P>0.05). The proportion of premature deaths among hepatitis C death cases was 55.88% and the mean age at death was (60.02±6.89) years. The proportion of premature deaths was higher in males (60.28%), laboratory-diagnosed patients (62.69%), patients with other liver diseases (72.06%), and patients non-compliant with follow-up (70.97%) compared to their respective counterparts (all P<0.05). Homemakers and unemployed patients (100.00%) and employed patients (88.89%) had a significantly higher proportion of premature deaths compared to retired patients (42.67%) (all P<0.001). There was a statistically significant difference in the distribution of causes of death between the premature death group and the non-premature death group(P=0.048). The leading three causes of premature deaths were malignant tumor (50.00%), HCV-related deaths (12.28%) and cerebrovascular diseases (10.53%). The causes of death that accounted for the highest proportions of premature death were other viral hepatitis (75.00%), followed by diabetes (71.43%) and HCV-related causes (70.00%). Males had a higher proportion of premature deaths than females for all causes of death except diabetes, liver cirrhosis, and HCV-related causes; however, none of these differences were statistically significant (all P>0.05). Conclusion The majority of hepatitis C death cases were male and retirees in Hongkou District, Shanghai. The leading cause of death was malignant tumor, while HCV-related death ranked as the fourth leading cause among hepatitis C death cases. Among premature deaths, HCV-related cause was the second most common cause following malignant tumor. With a premature death rate of 55.88%, factors such as sex, occupation, diagnostic classification, presence of other liver diseases, and follow-up compliance were significantly associated with premature deaths. It should be highlighted the importance of enhanced health management and targeted interventions in high-risk groups.