The National Institute for Communicable Diseases in South Africa participates in national laboratory-based surveillance for human isolates ofSalmonellaspecies. Laboratory analysis includes whole-genome sequencing (WGS) of isolates. We report on WGS-based surveillance ofSalmonella entericaserovar Typhi (SalmonellaTyphi) in South Africa from 2020 through 2021. We describe how WGS analysis identified clusters of enteric fever in the Western Cape Province of South Africa and describe the epidemiological investigations associated with these clusters. A total of 206SalmonellaTyphi isolates were received for analysis. Genomic DNA was isolated from bacteria and WGS was performed using Illumina NextSeq technology. WGS data were investigated using multiple bioinformatics tools, including those available at the Centre for Genomic Epidemiology, EnteroBase and Pathogenwatch. Core-genome multilocus sequence typing was used to investigate the phylogeny of isolates and identify clusters. Three major clusters of enteric fever were identified in the Western Cape Province; cluster one (n=11 isolates), cluster two (n=13 isolates), and cluster three (n=14 isolates). To date, no likely source has been identified for any of the clusters. All isolates associated with the clusters, showed the same genotype (4.3.1.1.EA1) and resistome (antimicrobial resistance genes:blaTEM-1B,catA1,sul1,sul2,dfrA7). The implementation of genomic surveillance ofSalmonellaTyphi in South Africa has enabled rapid detection of clusters indicative of possible outbreaks. Cluster identification allows for targeted epidemiological investigations and a timely, coordinated public health response.