Background: Crypt loss is a histological finding in acute gastrointestinal Graft‐Versus‐Host Disease (GI‐GvHD) of undefined clinical significance. Methods: Colonic crypt loss was graded in twenty‐three patients treated for GI‐GvHD following stem cell transplantation and then correlated with clinical parameters of disease severity and mortality. Results: Crypt loss was present in 17/23 cases, and in 11/23 cases crypt loss was deemed severe by the presence of contiguous areas of crypt loss. Nine of 11 patients with severe crypt loss had daily stool volumes in excess of 1000 ml/day, while only 3/12 of those with minimal or no crypt loss had this level of severe diarrhea. All 11 patients with severe crypt loss had a pathologic appearance at endoscopy and 10/11 had steroid refractory disease. Diarrhea resolved in only 3/9 patients with severe crypt loss. Five out of 10 patients (50%) with severe crypt loss expired within 15 months of diagnosis. All five deaths were attributable to the progression of GvHD itself or infection in the presence of continued GI‐GvHD. Conversely, only 1 of 12 patients (8%) with mild or no crypt loss had a death attributable to GvHD or infection. Conclusions: This study shows that severe colonic crypt loss predicts severe clinical GI‐GvHD that is more likely to be refractory to steroid treatment. In addition, crypt loss severity appears associated with higher mortality related to GvHD. Crypt loss can serve as a tool to predict clinically severe GI‐GvHD. Am. J. Hematol. 82:881–886, 2007. © 2007 Wiley‐Liss, Inc.