Helicobacter pylori (H. pylori) is the most common human bacterial infection worldwide, infecting approximately half of the world's population. Although antibiotic use is indicated for H. pylori eradication, the recommended type of antibiotic varies from country to country according to the H. pylori resistance pattern; developing countries, such as Egypt, may have different patterns than developed countries. We evaluated the antibiotic resistance of H. pylori in Egypt. Methods: This cross-sectional study included 134 adult patients with upper gastrointestinal (GI) complaints. Patients with a history of PPI during the last 2 weeks or antibiotics during the last 4 weeks before endoscopy were excluded. Upper GI endoscopies were performed and biopsies were collected for histopathology and H. pylori culture. Demographic, clinical, and endoscopic data were also collected. Antimicrobial susceptibility testing for H. pylori was performed for nine therapeutically relevant antibiotics using the Kirby-Bauer disc diffusion method. Results: The H. pylori antibiotic resistance rates were as follows: moxifloxacin, 10%; doxycycline, 15%; levofloxacin, 20%; clarithromycin, 40%; azithromycin, 40%; erythromycin, 65%; rifampicin, 90%; amoxicillin, 95%; and metronidazole, 100%. Dual resistance rates were 40% for amoxicillin/clarithromycin, 40% for metronidazole/clarithromycin, and 95% for amoxicillin/metronidazole. Conclusion:In Egyptian patients, H. pylori had >90% resistance to metronidazole and amoxicillin; modest resistance to erythromycin, azithromycin, and clarithromycin; and low resistance to moxifloxacin, and levofloxacin (≤20%). Dual resistance was high for amoxicillin/clarithromycin and amoxicillin/metronidazole, which prefers using quinolones rather than clarithromycin or metronidazole for first-line treatment of H. pylori in Egypt.