Background: Helicobacter pylori (H. pylori) is a gram-negative bacterium, producing gastric ulcer, mild to severe gastritis, gastric carcinoma and lymphoma to the gastric mucosa-associated lymphoid tissue through many virulence influences. Among the virulence factors identified; vacuolating cytotoxin A (vacA) and cytotoxin-associated gene A (cagA) play an important role. Objective: In this study, we try to discover the relation between vacA variant and cagA genes with the clinical illness occurring in H. pylori patients Methodology: One hundred and forty patients were included in our study. Dual biopsy samples were taken from the stomach; one was examined by the urease test, and the other one was stored at −80°C for DNA extraction followed by PCR. The existence of H. pylori in the tissue was recognized by the existence of glmM gene and its detection by PCR. All the positive samples were additionally tested by PCR for the occurrence of cagA and vacA variant genes. Results: Our study demonstrated that cagA and vacA genes were found among 50% and 57% respectively of H. pylori patients complaining from gastrointestinal illnesses and that vacA s1/s2 was the main genotype found in H. pylori persons with gastroduodenal disease. Significant relation between vacA s1 gene and cagA gene was found. Conclusion: vacA s1 genotype has a vital role in upper gastrointestinal illnesses progress.