Background: Typhoid fever is endemic in developing countries including Egypt, producing major public health problems with high mortality and morbidity. The emergence of resistant serovar Typhi (S. typhi) to commonly recommended antimicrobials is alarming in developing countries. Fluoroquinolones have been the empirical drug of choice for multidrug-resistant MDR typhoid. However, there have been several alarming reports of fluoroquinolones therapeutic failure in typhoid patients. Resistance of S. typhi to fluoroquinolones commonly results from target site mutation. Objectives: Determination of antimicrobial resistance pattern of S. typhi isolated from Egyptian patients with typhoid fever admitted to or attended Mansoura University Hospitals (MUHs) and Mansoura Fever Hospital, detection of quinolones resistant strains and using PCR-RFLP and sequencing techniques for testing mutation at QRDR of gyrA gene in the isolated strains. Methodology: Blood and Stool samples from clinically suspected typhoid patients were screened by culture on suitable media and were identified biochemically. The identified S. typhi isolates were tested for susceptibility to antimicrobials using the Kirby Bauer disk diffusion method. Minimum inhibitory concentrations of ciprofloxacin were determined by E test. Interpretation of all results was done according to the CLSI guidelines 2015. Mutations in gyrA gene were detected by PCR-RFLP and sequencing methods. Results: Out of 500 blood and stool samples, 57 isolates were S. typhi (96.6%) and only two were S. paratyphi A (3.4%). Of the 57 S. typhi, 80.7% were resistant to nalidixic acid, 50.9% had ciprofloxacin MIC 0.125-0.5 μg/ml and 19.3% had ciprofloxacin MIC >1 μg/ml. Ser 83 mutation in gyrA was detected in 63.1% of the isolates. Conclusion: Increased emergence of fluoroquinolones -resistant typhoidal Salmonella in Egypt which is caused mainly by point mutation at codon 83 (Ser83-Phe substitution TCC→TTC) in QRDR of gyrA gene.