<b>Background:</b> Typhoid fever is a major public health concern in developing countries. The upsurge in the occurrence of bacterial isolates that are resistant to nalidixic acid;with reduced susceptibility to ciprofloxacin in typhoidal <i>Salmonellae</i> constitutes a challenge to the clinician. <b>Methods:</b> In order to better understand the epidemiology of <i>Salmonella</i> infections in South India, <i>Salmonella typhi</i> isolates were screened from various healthcare centers. <i>Salmonella</i> isolates were identified by using standard phenotypic, serological, antibiotic susceptibility and molecular methods. <b>Results:</b> Among a total of 100 <i>S. typhi</i> isolates 9% were found to be multidrug resistant and 30% were nalidixic acid resistant. Isolates with reduced susceptibility to ciprofloxacin displays single base mutations in the gyrA gene. A very low rate of 1% resistance was found to ciprofloxacin. The only one isolate with ciprofloxacin MIC ≥ 4 μg/ml also showed single mutation in the QRDR of the gyrA gene in <i>S. typhi</i> (GenBank accession no. HQ176349-HQ176368). <b>Conclusions:</b> A very low rate of nalidixic acid resistance with reduced susceptibility to ciprofloxacin was observed in comparison to other endemic areas in isolates of <i>S. typhi</i> from Gulbarga, South India, with steadily increasing NAR <i>S. typhi</i> but decreasing MDR isolations over the study period. This is most likely due to an increased use of ciprofloxacin as a first line drug of choice over more traditional antimicrobial agents for the treatment of typhoid fever.