Infantis has recently become one of the most common serotypes of Salmonella isolated in the U.S. from raw meat samples collected in processing facilities and in retail stores. Investigations have determined that the majority of these isolates contain the pESI plasmid, but there has not been a large-scale investigation of the chromosome of these isolates. Here, we investigated 3276 whole-genome sequences of Salmonella Infantis with and without the pESI plasmid to understand chromosomal differences between plasmid carriage groups. S. Infantis genomes arranged into multiple clades with a single clade containing the isolates carrying the plasmid. Fifty-eight SNPs were identified in complete linkage disequilibrium between isolates that did and did not carry the plasmid. However, there were no unique genes present only in the genomes of isolates containing the plasmid. On average, isolates with the plasmid did contain more insertion sequences than those without (p < 0.05). Given that S. Infantis isolates carrying pESI form a single clade, it can be inferred that the increase in carriage of this plasmid in the U.S. is due to rapid clonal expansion of a single strain rather than as a result of multiple transfer events. As this S. Infantis clone does not contain any unique chromosomal genes, its proliferation appears to be due to pESI plasmid-encoded genes that may be advantageous in the chickens and turkeys or in their environment.