Introduction: It has been noted in the literature that cavernous transformation of the portal vein (CTPV) can cause pancreatic duct atrophy, probably by enhanced collateral formation, but the clinical significance of this has not been established. Aims: To evaluate whether CTPV affects the pancreatic exocrine functions. Methodology: Eighteen patients with CTPV were identified and prospectively studied. In these cases, despite a full clinical, biochemical, radiologic, and hematological evaluation, we found no etiologic factor for thrombosis in the portal vein (PV). All patients underwent a detailed evaluation for pancreatic morphology and pancreatic exocrine functions. In all cases, abdominal Doppler ultrasonography (US), abdominal spiral computed tomography (CT), and endoscopic retrograde cholangiopancreatography (ERCP) were performed for evaluation of pancreatic morphology. For the purpose of this study, serial biochemical tests, including measurement of serum amylase, pancreatic amylase, lipase, glucose, calcium, and lipids, were performed every 3 months. All 18 patients also underwent a bentiromide test to determine whether there was any exocrine pancreatic insufficiency. The findings were compared with those for 20 healthy control subjects and reference controls. Results: For all 18 patients with idiopathic CTPV and all controls, ERCP was performed successfully. The pancreatic duct was determined to be smaller than in control subjects and in a reference control group (p < 0.05). In this group serum pancreatic amylase, alkaline phosphatase, and direct bilirubin levels were found to be higher than in controls, and statistically important differences between the two groups (p < 0.05) were documented. In all 18 subjects the bentiromide test was well tolerated and was performed successfully. For 15 of them (83%), we found that urinary excretion of para-amino benzoic acid (PABA) was significantly less than in control subjects and the reference control group) < 0.05). Conclusion: Pancreatic duct atrophy in patients with CTPV is clinically significant. When clinical signs are not manifest and routine biochemical tests are not useful for detecting exocrine pancreatic insufficiency, the bentiromide test is highly sensitive and specific for detecting probable pancreatic insufficiency in patients with CTPV.