Background and Aim of This Study. Itch frequently occurs in patients with chronic cholestasis. However, it remains unclear why some patients do and others do not develop pruritus. In addition, drug treatment is frequently ineffective. We repeatedly observed that cholestatic patients without itch had a relatively high serum gamma-glutamyl transpeptidase (GGT), relative to their serum bilirubin. The aim of this study was to validate this clinical observation. Methods. We included 235 patients with chronic extrahepatic cholestasis due to pancreatic cancer, cholangiocarcinoma, or papillary carcinoma. Results. GGT was significantly higher in patients without pruritus (median 967, IQR 587–1571) compared to patients with pruritus (median 561 IQR 266–1084 IU/l) ( p < 0.01 ). In contrast, median alkaline phosphatase (AP) was 491 U/L (IQR; 353–684) in patients with pruritus and was not significantly different from 518 U/L (IQR; 353–726) in patients without pruritus ( p = 0.524 ). Direct bilirubin was significantly higher in patients with pruritus compared to patients without pruritus (168 μmol/L (IQR; 95–256) vs. 120 μmol/L (IQR; 56.75–185.5)) ( p < 0.01 ). After correcting for the extent of cholestasis via direct bilirubin, the negative association between GGT and pruritus remained significant and became stronger ( p < 0.001 ). Conclusion. Serum GGT activity is inversely associated with the presence of cholestatic itch in patients with chronic extrahepatic cholestasis.