INTRODUCTION: Cannabis continues to be legalized in the United States and there is also increasing inconclusive evidence about the impact of cannabis in acute pancreatitis (AP). The aim of this study was to investigate the impact of cannabis use among all patients with AP. METHODS: We queried a commercial database (Explorys Inc, Cleveland, OH, USA), an aggregate of electronic health record data from 26 major integrated US healthcare systems. We identified a cohort of patients with a Systematized Nomenclature of Medicine—Clinical Terms (SNOMED-CT) diagnosis of AP. We then identified cannabis-user (CU) patients and compared them with non-CU. Logistic regression models were constructed. RESULTS: Of the 62,817,650 individuals in the database, we identified 308,350 (0.49%) individuals with AP. Out of those, 14,740 (0.05%) individuals were CU. Interestingly, CU were more likely to be male [OR 1.79; 95% CI: 1.73–1.85, P < 0.0001], African American [OR 2.55; 95% CI: 2.46–2.64, P < 0.0001], younger (<65 years old) [OR 9.49; 95% CI 8.86–10.16, P < 0.0001], tobacco smokers [OR 2.08; 95% CI: 1.98–2.19, P < 0.0001], alcohol consumers [OR 2.00; 95% CI: 1.94–2.07, P < 0.0001] and obese [OR 1.13; 95% CI: 1.08–1.19, P < 0.0001] (Table 1, Figure 1). CU were more likely to have SIRS [OR 1.43; 95% CI: 1.37–1.49, P < 0.0001], AKI [OR 1.45; 95% CI: 1.40–1.50, P < 0.0001], acute respiratory failure [OR 1.45; 95% CI: 1.38–1.51, P < 0.0001], ileus [OR 1.28; 95% CI: 1.20–1.37, P < 0.0001], shock [OR 1.23; 95% CI: 1.16–1.32, P < 0.0001], sepsis [OR 1.31; 95% CI: 1.23–1.39, P < 0.0001], altered mental status [OR 2.00; 95% CI: 1.90–2.10, P < 0.0001], enteral tube feeding requirement [OR 1.46; 95% CI: 1.34–1.60, P < 0.0001], portal vein thrombosis (PVT) [OR 1.35; 95% CI: 1.17–1.56, P < 0.0001], pulmonary embolism (PE) [OR 1.21; 95% CI: 1.12–1.31, P < 0.0001], to receive opiates [OR 1.87; 95% CI: 1.79–1.96, P < 0.0001], to undergo abdominal CT scan [OR 1.59; 95% CI: 1.54–1.64, P < 0.0001], and less likely to have cholangitis [OR 0.35; 95% CI: 0.31–0.41, P < 0.0001], to undergo MRCP [OR 0.65; 95% CI: 0.57–0.75, P < 0.0001], ERCP [OR 0.51; 95% CI: 0.48–0.55, P < 0.0001] (Table 2). CONCLUSION: Cannabis users have worse outcomes in AP and this could be potentially explained by tobacco smoking, obesity and alcohol consumption rates that were higher in CU. Further studies to corroborate our findings are needed, especially looking at the route, frequency, modality and amount of cannabis intake in patients with AP.