Background: Helicobacter pylori (H. pylori) plays a crucial role in the pathogenesis of gastroduodenal diseases. Eradication of H. pylori has been shown to reduce the risk of recurrent peptic ulcer diseases and even the development of gastric cancer. Clarithromycin based triple therapy for 7 to 14 days is currently the first line therapy. Resistance to clarithromycin is the major reason for eradication failure. Therefore, the detection of antibiotic resistance is crucial in the management of H. pylori infection. The aim of this study was to determine the eradication rate ofH. pyloriin SMH outpatients with chronic gastritis exposed to different risk factors and to assess the effect of clarithromycin resistance onH. pylorieradication using FISH technique and comparing the results with conventional PCR and E-tests. Methods: Seventy two patients were tested in this study suffering from chronic dyspepsia and were all; C13 Urea breath test positive and H. pylori antigen in stool positive, then they received triple therapy (clarithromycin, amoxil and omeprazole) for 14 days. FISH, PCR and bacteriologic cultures from gastric biopsies were conducted on all patients with failure of therapy, biopsies were fixed in liquid nitrogen. After mounting of frozen sections on microscopic slides, they were hybridized with oligonucleotide probes for detection of clarithromycin-resistantH. pylori.Susceptibility of cultured strains ofH. pylorito clarithromycin was also determined by the E-test and also PCR was carried out using clarithromycin resistance primer and the results were compared. Results: H. pyloriwas eradicated in 38 patients (52.7%) [Negative for C13 urea breath test and Ag in stool (P< 0.05)]. Of the remaining persistently infected 34 patients (positive for both C13 urea breath test and H. pylori Ag in stool), gastric biopsy specimens were examined by FISH which were all (100%) positive forH. pylori.FISH, also, showed that 14 strains (41.2%) were susceptible to clarithromycin and 20 strains (58.8%) were resistant. There was no discrepancy between E-test and FISH technique for detection of resistant strains ofH. pylori, except for the time factor.PCR also didn’t show discrepancy with either FISH or E-test except for being costly. Conclusion: Clarithromycin resistance is a rapidly evolving problem at Mansoura which contributes to failure of H. pylori therapy and alternatives such as erythromycin and rifamycin derivatives with newpolycycliccompounds or combined lines of treatment is highly required.FISH is a rapid and sensitive technique for primary detection ofH. pyloriand also for detection of strains susceptible to clarithromycin in clinical samples. Therefore, it is a suitable method for determination of susceptibility ofH. pylorito clarithromycin, especially when a quick decision is necessary for treating chronic dyspeptic patients at high risk