Background: Increasing antibiotic resistance by pathogenic bacteria is observed in poor sanitary conditions. The peak incidence of typhoid occurs between 5-15 years of age. This is the most common bacteraemic illness of children in Pakistan. The aim of this study was to investigate the frequency of drug-resistant Salmonella Typhi and S. Paratyphi A in children hospitalized or treated as outpatients at a tertiary care centre that serves Gadap Town, an extensive slum district of Karachi. Methods: A total of 275 peripheral blood samples were collected from children up to 14 years old who presented with clinical features of typhoid to Fatima Hospital, Baqai Medical University, over a two-year period. Samples were cultured for growth of aerobic and facultative anaerobic bacteria, identified by biochemical reactions. Antimicrobial susceptibility was tested by Kirby-Bauer disc diffusion using eight different antibiotics. Results: Among all samples, 30 (10.9%) were positive for S. Typhi by blood culture. The rate of positivity was 23 (76.7%) cases for ages 5-14 years, three (10.0%) in each of age groups 2.0-2.9 and 4.0-4.9 years, and one patient (3.3%) aged 3.0-3.9 years. The majority of S. Typhi isolates were resistant to co-trimoxazole (66.7%), ampicillin (63.3%), nalidixic acid (60.0%), chloramphenicol (50.0%) and aztreonam (50.0%). However, most isolates were susceptible to ceftriaxone (76.7%) and ciprofloxacin (66.7%). There were 15 multidrug-resistant isolates but no typhoid-related deaths. Conclusion: Our findings show evidence of antimicrobial resistance by S. Typhi isolated from Karachiite children living in a poverty-stricken setting where water quality and sanitation are both unsatisfactory. Currently, Pakistan's most populated city is recognized as a focus of typhoid cases. Therefore, this first report of the emergence of confirmed cases of multidrug-resistant S. Typhi from the only public hospital in its largest neighbourhood identifies a grave public health concern.