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Salmonella Paratyphi A, one of the major etiologic agents of enteric fever, has increased in prevalence in recent decades in certain endemic regions in comparison to S. Typhi, the most prevalent cause of enteric fever. Despite this increase, data on the prevalence and molecular epidemiology of S. Paratyphi A remain generally scarce. Here, we analysed the whole genome sequences of 216 S. Paratyphi A isolates originating from Kathmandu, Nepal between 2005 and 2014, of which 200 were from patients with acute enteric fever and 16 from the gallbladder of people with suspected chronic carriage. By exploiting the recently developed genotyping framework for S. Paratyphi A (Paratype), we identified several genotypes circulating in Kathmandu. Notably, we observed an unusual clonal expansion of genotype 2.4.3 over a four-year period that spread geographically and systematically replaced other genotypes. This rapid genotype replacement is hypothesised to have been driven by both reduced susceptibility to fluoroquinolones and genetic changes to virulence factors, such as functional and structural genes encoding the type 3 secretion systems. Finally, we show that person-to-person is likely the most common mode of transmission and chronic carriers seem to play a limited role in maintaining disease circulation. Author summary: Enteric (typhoid) fever is caused by bacteria of Salmonella enterica species, specifically Salmonella Typhi and Salmonella Paratyphi A. While the former is most commonly identified as the causative agent of enteric fever, S. Paratyphi A is increasing in prevalence in many endemic areas like Nepal. However, the understanding of the phylogenetic structure and population dynamics of this organism, as well as transmission patterns, remains incomplete. Here, we provide a detailed phylogenetic analysis of S. Paratyphi A isolated from enteric fever patients in Nepal through whole genome sequence analysis, combined with epidemiological observations, such as water source use, and chronological and location data. We observed an unusual expansion of a genotype (genetic ID) that replaced other genotypes in the area, indicative of changes in circulating population composition. This expansion is hypothesised to have been driven by reduction in antibiotic susceptibility and changes on bacterial structures that are important for pathogenicity. Our data also suggest person-to-person as the most likely mode of transmission for this pathogen. Understanding of S. Paratyphi A population structure, sources of infection, and transmission will help develop policies for enteric fever management, particularly prior to vaccine introduction, as changes in population composition may affect vaccine efficacy. [ABSTRACT FROM AUTHOR]