Background: Exocrine pancreatic insufficiency (EPI) is characterized by inadequate secretion of digestive enzymes. EPI is associated with increased risk for pancreatic cancer as well as increased risk for diabetes and consequently cardiometabolic (CM) risk equivalents. Emerging data suggest patients with cancer also have increased CM risk equivalents. To explore the cardiovascular risk associated with both EPI and cancer, we sought to describe and compare CM comorbidities and surrogates in patients with EPI vs cancer. Methods: A retrospective observational electronic chart analysis was done at Ochsner Health, Louisiana, spanning records from January 2017-2020 comparing two cohorts: patients with EPI (n=677) and patients with Cancer (n=1432). Results: The Cancer cohort was older (65.1 ± 11.9 yrs) than the EPI cohort (54.2 ± 17.6 yrs) (p < 0.05). The Cancer cohort had higher AST levels (63.2 ± 106.2 U/L [nl 8-33 U/L] at start, 84.9 ± 447.3 U/L at end) vs the EPI cohort (50.2 ± 86.9 U/L at start, 65.4 ± 368.9 U/L at end) (p < 0.05). The Cancer cohort also had higher ALT levels (69 ± 111.4 U/L (nl 7-55 U/L) at start, 58.5 ± 141.2 U/L at end) vs the EPI cohort (48.7 ± 79.5 U/L at start, 41.4 ± 100.3 U/L at end) (p < 0.05). No significant differences were seen in Cancer cohort vs EPI cohort for A1c, TG, amylase, lipase, cholesterol, uric acid, tobacco/alcohol use, or blood pressure levels. Within the Cancer cohort, there was an increase in neuropathy (11% at the start vs 26.9% at end [p < 0.05]), CHF (3.63% at the start vs 11.5% at end [p < 0.05]), and HTN prevalence (29.9% at the start vs 66.1% at end [p < 0.05]). Cancer patients also had decreased weight (175.2 ± 46.5 lbs at start, 163.8 ± 43.4 lbs at end [p < 0.05]) and BMI (27.3 ± 6.5 at start, 25.7 ± 6.4 at end [p < 0.05]). Among the general cancer cohort, no statistically different changes were seen in hypoglycemia, DKA, retinopathy, nephropathy, ESRD, dialysis, HLD, NAFLD, OSA, CAD, CVD, PAD, hyperuricemia, or gout prevalence over the period of observation or in comparison to EPI cohort. Conclusions: Patients in the Cancer cohort in this study have some indices of greater CM risk compared to those with EPI. Though older, they had significantly higher AST and ALT levels compared to EPI cohort. Over the 3 years of observation, cancer patients developed a statistically significant increase in neuropathy, CHF, and HTN prevalence, and decrease in weight and BMI. These changes may reflect consequent morbidity related both to natural disease progression and/or effects of cancer treatments such as chemotherapy.