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 SalmonellaTyphi 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. Typhiby 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. Typhiisolated 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 neighborhood identifies a grave public health concern.