Objectives: To determine the effect of lansoprazole and high dose ranitidine on the accuracy of the¹⁴ C-urea breath test (UBT). Using intragastric pH recordings, we correlated the effect of these agents on the UBT with their potency of gastric acid suppression. Methods: Patients with active Helicobacter pylori infection underwent a baseline UBT before receiving 14 days of lansoprazole (30 mg/day) or ranitidine (300 mg bid). During therapy, patients were asked to undergo 24-h intragastric pH monitoring. Repeat breath testing was performed 1 day after completion of the study drugs. If the UBT was equivocal or negative (¹⁴ CO₂ excretion was < 200 dpm), further UBTs were completed until the¹⁴ CO₂ excretion was > 200 dpm. Results: Thirteen patients received lansoprazole. Eight of thirteen patients developed a negative or equivocal UBT. All patients had¹⁴ CO₂ excretion > 200 dpm 5 days after the cessation of lansoprazole. Eleven patients received ranitidine. Ranitidine led to equivocal or false negative UBTs in 2 of 11 cases. This effect resolved within 5 days of stopping ranitidine. Intragastric pH recordings revealed that the patients who experienced the most profound gastric acid suppression were those that developed equivocal or false negative UBTs. Conclusions: Lansoprazole significantly affected the accuracy of the UBT, causing equivocal or false negative results in 61%. High dose ranitidine affected the breath test in only 18%. The ability of these drugs to suppress gastric acid secretion predicted those patients who developed equivocal or false-negative UBTs. The effect on the accuracy of the UBT resolved within 5 days of drug cessation.