Rapid urease tests are widely used at endoscopy to determine the presence of Helicobacter pylori infection. In this prospective study, we compared the accuracy of two rapid urease tests, CLOtest and PyloriTek, using histology as the gold standard. Histologic staining was performed using both H&E and Giemsa, and all slides were reviewed by a single pathologist who was blinded to the results of the rapid urease tests and endoscopic findings. One hundred two patients were enrolled; their mean age was 59 years (range 16 to 95 years), and there were 45 males and 57 females. Histology confirmed the presence of H. pylori infection in 39% of patients. The proportions of false positives for CLOtest (8.0%) and PyloriTek measured at 1 hr (29.0%) were significantly different (Z = 2.90, P = 0.0038). No significant difference was seen between the proportions of false negatives. We conclude that the clinical usefulness of PyloriTek urease test is limited by its lack of specificity.