We report the first description of sevelamer crystals (Renagel and Renvela, Genzyme; phosphate-lowering agents) in the gastrointestinal tract. We prospectively collected cases with novel, histologically identical crystals from 4 major academic centers over a 1-year period and studied pertinent clinicopathologic features. Sevelamer usage in the setting of chronic kidney disease was demonstrated in all cases (n=15 total cases, 7 patients). Sites of involvement included the esophagus (n=2), small bowel (n=2), and colon (n=11). The background mucosa was normal in only 1 case. Notable mucosal abnormality included chronic mucosal damage (n=5), acute inflammation (n=4), inflammatory polyp (n=2), extensive ulceration (n=2), ischemia (n=1), and necrosis (n=1). In general, sevelamer crystals displayed broad, curved, and irregularly spaced “fish scales” with a variably eosinophilic to rusty brown color on hematoxylin and eosin (H&E) staining and violet color on periodic acid-Schiff-alcian special staining with diastase (PAS/D). To validate these findings, sevelamer tablets (Renvela) were crushed and submitted for histologic processing; the findings were identical to those in the patient specimens. The possibility of Kayexalate (sodium polystyrene sulfonate) and cholestyramine had been raised in error. However, Kayexalate has narrow, rectangular “fish scales” and is violet on H&E and magenta on PAS/D; cholestyramine lacks internal “fish scales,” is bright orange on H&E, variably gray or hot pink on PAS/D, and is unassociated with mucosal injury. Further study is required to determine whether sevelamer plays a causal role in these injuries; however, its crystal is an important mimic of both Kayexalate and choleystyramine. As the history of sevelamer administration was not documented in any pathology requisition, awareness of sevelamer’s characteristic morphology is crucial to avoid the diagnostic pitfalls of its mimics.