Helicobacter pylori (H. pylori) and nonsteroidal anti-inflammatory drugs (NSAID) are the most common pathogens in the gastroduodenal mucosa in animals and humans, but their relationship in ulcerogenesis has been little studied. According to some authors, H. pylori infection in humans does not act synergistically with NSAID on ulcer healing, therefore, there is no need to eradicate the germ. This notion is supported by the finding that the eradication of H. pylori does not affect NSAID-induced gastropathy treated with omeprazole and that H. pylori infection induces a strong cyclooxygenase-2 expression resulting in excessive biosynthesis of gastroprotective prostaglandins, which should in turn counteract NSAID-induced gastropathy and heal the existing ulcer. Other investigators claim that H. pylori infection acts synergistically with NSAID on ulcer development, therefore, H. pylori should be eradicated, particularly at the start of long-term NSAID therapy. Maastricht 2-2000 consensus also recommends eradication prior to NSAID treatment, but this eradication does not appear to accelerate ulcer healing or to prevent the recurrent ulcers in NSAID users. Our studies in almost 6000 dyspeptic patients undergoing upper endoscopy and [13C]-urea breath test (UBT) revealed that about 70% of these patients are H. pylori (+) and about 30.6% of these develop gastroduodenal ulcers. Of these ulcers, over 70% were H. pylori (+) positive, 12% NSAID (+), 8% were both H. pylori (+) and NSAID (+), while 22% ulcers were H. pylori (−) and NSAID (−) or “idiopathic” ulcers. Basically, our results support Hawkey's concept and this also agrees with our findings in the rat model showing that: (1) there is no synergistic interaction between H. pylori infection and NSAID on gastric ulcer development, (2) H. pylori and NSAID are independent risk factors for peptic ulceration, and (3) NSAID therapy in H. pylori positive patients attenuates the ulcer development possibly due to direct inhibitory action of these drugs on H. pylori.