Determination of plasma levels of vasoactive intestinal polypeptide (VIP) has been used for screening patients with chronic diarrhea to identify potential neuroendocrine tumors. This 6-year blinded study from 1981 to 1986 examines the causes of elevated VIP levels in patients. In healthy volunteers (n = 144), VIP concentrations ranged from 14 to 76 pg/mL (mean ± SE, 28 ± 12), whereas in chronic renal failure, 4 of 34 patients or 12% [serum creatinine 4.5–9.0 mg/dL (397–795 μmol/L)] had an elevation to > 100 pg/mL. No patient with idiopathic hepatic cirrhosis (n = 12) had elevation of serum concentration of this peptide. Among 588 consecutive unselected patients undergoing evaluation for chronic diarrhea (n = 362; 62%) or possible neuroendocrine tumor (n = 214; 36%), 23 patients (3.9%) had concentrations >76 pg/mL. In this group, 5 patients had functioning (VIP, 160–5975 pg/mL) and 5 had nonfunctioning (VIP, 80–120 pg/mL) pancreatic islet cell carcinomas: all 10 patients had hepatic metastases. Other known causes of elevated levels of VIP, ranging from 80 to 340 pg/mL, included other neurogenic tumors (n = 3), small- bowel resection (n = 2), inflammatory bowel disease (n = 2), chronic renal failure (n = 1), and prolonged fasting (n = 1). Patients with diarrhea in which VIP-secreting tumors were identified had plasma vasoactive intestinal peptide concentrations >140 pg/mL. In patients with chronic diarrhea, determination of plasma vasoactive intestinal peptide levels did identify tumors secreting this peptide, but the results from this referral institution did not show identification of these tumors early in their clinical course.