The diagnostic yield of various tests for Helicobacter pylori infection in Patients on acid-reducing drugs, such as proton pump inhibitors (PPI) and histamine-2 receptor blocker (H2RB), was compared. Seventy-four consecutive Patients on acid-reducing drugs were enrolled: 34 (46%) were on PPIs, 20 (27%) were on H2RBs and 20 (27%) were not on medications. For those Patients on PPIs, RUT and histology results from antrum were negative in 28 (82%) and 17 (50%) Patients, respectively (OR: 4.7, 95% CI: 1.4-16.6, P = 0.004), while those from the corpus were negative in was 28 (82%) and 18 (53%) Patients, respectively (OR: 4.4, 95% CI: 1.3-15.5, P = 0.006). For Patients on H2RBs, RUT and histology results from the antrum were negative in 12 (60%) and six (30%) Patients, respectively (OR: 3.5, 95% CI: 0.8-16.1, P = 0.05), while those from the corpus were negative in 12 (60%) and nine (45%) Patients, respectively (OR: 1.8, 95% CI: 0.4-7.8, P = 0.342). For those Patients on PPIs, the diagnostic yield of both RUT and histology was reduced from both the antrum and corpus. In these Patients, PCR for H. pylori is more sensitive than RUT and histology.