Background: Chronic and acute pancreatitis are established risk factors for pancreatic cancer. Chronic pancreatitis and pancreatic cancer are also common causes of exocrine pancreatic insufficiency (EPI), which is characterized by inadequate pancreatic secretion of exocrine digestive enzymes. Although the association between EPI and pancreatic cancer has been thought to be linked by preceding chronic pancreatitis, it is unclear if EPI, regardless of etiology, is a risk factor or early marker for pancreatic cancer or cancer in general. Methods: This is a retrospective observational study utilizing the electronic health records of Ochsner Health System, Louisiana, over a 3-year period from January 2017 to January 2020 to identify patients with a diagnosis of EPI by ICD-10 codes. Two cohorts were reviewed: patients with EPI (n=677) and patients with pancreatitis (n=1852). Both history of acute and/or chronic pancreatitis were included in the pancreatitis cohort. The cohorts were compared based on cancer prevalence at the start and end of the 3 year observation period. Results: In the EPI cohort, the cancer prevalence was 15.95% (108) at start, and 43.9% (297) at end, (p<0.05); and pancreatic cancer prevalence at start was 6.65% (123) and 29.8% (552) at end (p<0.05). In the pancreatitis cohort, the cancer prevalence was 5.4% (100) at start and 15.9% (294) at end (p<0.05); and pancreatic cancer 0.8% at start and 5% at end (p<0.05). Conclusions: Over a 3 year period, the rise in prevalence of general cancer and pancreatic cancer was higher in the EPI cohort compared to the pancreatitis cohort. Additionally, there was a statistically significant 2.8-fold increase in prevalence of cancer diagnosis and 4.5-fold increase in prevalence of pancreatic cancer diagnosis in the EPI cohort over the 3 year observation period. Though this is an observational study, it suggests the possibility that EPI, regardless of etiology, may be an independent predictor/risk factor for the development of future cancer in general and pancreatic cancer in particular. In addition it appears that this risk potential is substantively greater than that from a history of pancreatitis alone.