In this study, we assessed whether standard doses of antiulcer drugs rebamipide, and ecabet sodium influence the accuracy of the urea breath test (UBT). Without medication, values of UBT estimated with nondispersive isotope-selective infrared spectrometry did not significantly change during follow-up (average 4.4 months). Then, we randomized 21 H. pylori-positive patients without serious disease to receive either rebamipide or ecabet sodium for 28 days. UBT was performed at baseline, on day 14, on day 28, and 2 weeks after cessation of drugs. On day 14, the median value of UBT declined significantly (p = 0.0113) compared to baseline with ecabet sodium but not with rebamipide. This caused a false-negative result of UBT in one of 11 patients who received ecabet sodium. The decline of UBT resolved 2 weeks after drug cessation. In addition, we performed a crossover study in 11 H. pylori-positive volunteers with these drugs, and ecabet sodium but not rebamipide significantly reduced UBT values (p = 0.0058). These findings indicate that ecabet sodium adversely influences the accuracy of UBT and that the withdrawal of this drug before testing appears to be necessary to avoid false-negative results.