e16210 Background: Primary gallbladder cancer is a rare but aggressive cancer with poor outcomes. Our study aims to understand the survival trends of patients with Primary gallbladder cancer (PGC) and analyze the prognosis factors based on cases registered in the SEER database from 2000 to 2020. Methods: We usedSEER*Stat Version 8.4.3 software to extract primary gallbladder carcinoma cases from SEER 17 registries (2000-2020). 20,143 patients were included in the study. Those with unconfirmed histology were excluded. We analyzed overall mortality and primary gallbladder cancer-specific mortality (CSM) using a Cox proportional hazards model. The survival analysis was carried out using the Kaplan–Meier method and the log-rank test was used to compare survival curves. Results: There was an overall increase in gallbladder cancer cases by 23% in 2010-2020 compared to 2000-2010. There was no significant cancer-specific mortality difference identified between males and females (HR = 1.009; CI: 0.972-1.046). Non-Hispanic blacks had higher overall mortality (HR = 1.134; CI: 1.010-1.273) amongst different ethnicities. Crude analysis revealed overall mortality was higher among patients aged above 80 years (HR = 9.857; CI: 6.257-15.528). Crude analysis also revealed significantly higher cancer-specific mortality for cholangiocarcinoma (HR = 1.622; CI:1.509-1.744) amongst histological subtypes. Gallbladder cancer-specific mortality was high with regional disease (HR = 3.115; CI: 2.839-3.419) and increased significantly with distant metastases (HR = 7.169; CI 6.512-7.891). Treatment with surgery, chemotherapy, or radiation alone or in combination improved survival among patients. Conclusions: There is a significant increase in gallbladder carcinoma mortality even among patients with regional disease, and it was worse with metastatic disease. With limited early-stage diagnoses and poor overall survival rates, we recommend further research to develop effective screening methods, understand risk factors, and explore effective preventive and therapeutic strategies for primary gallbladder cancer.