Background: The treatment of 21st Century XDR typhoid fever is potentially life-threatening and endemic in Pakistan, presents a therapeutic challenge as currently there is no universal treatment strategy whether to use monotherapy with meropenum or a combination of meropenum and azithromycin. Our objective was to compare the efficacy of both therapies in complicated XDR typhoid fever in children, regarding defervescence, bacterial clearance time, resolution of complications, hospital stay, and relapse.  Methodology: This open-label randomized comparative trial was conducted over 18 months at the Department of Pediatrics, Kemari, Clifton and North Campuses, Ziauddin University Hospital Karachi, Pakistan, in which children (aged 6 months to 18 years) with positive blood culture for XDR enteric fever, were recruited into 2 parallel treatment groups (meropenum) and (meropenum+azithromycin combined). Primary outcome viz clinical improvement (resolution of defervescence, complications, and hospital stay) and lab improvement (negative repeat blood culture, 5 days post-treatment), as well as secondary outcome i.e. treatment failure, adverse drug reactions, and relapse of typhoid within 2 weeks post-treatment were monitored. Results: In the combination group, there was a quicker resolution of fever (5.40 ± 2.17 days vs 6.55 ± 2.77 days in the monotherapy group) as well as complications (3.42 ± 1.97 days vs 4.31 ± 2.71 days in the monotherapy group), resulting in shorter hospital stay (6.94 ± 2.63 days vs 8.08 ± 3.16 days in monotherapy group). 20% had treatment failure in the monotherapy group with a relative risk of 3.55 times more than that in the combination group.   Conclusion: Combination therapy with meropenum and azithromycin is more efficacious in treating complicated XDR typhoid fever in children than meropenum alone.