Salmonella enterica subsp. enterica serovar Napoli (S. Napoli) ranks among the top serovars causing human infections in Italy, although not common in other European countries. Isolates are generally pan-susceptible or resistant to aminoglycosides only, however data on antimicrobial resistance genes in strains of S. Napoli are limited. Recently an isolate encoding resistance to third generation cephalosporins was reported. This study aimed to characterize plasmid-encoded cephalosporin resistance due to the bla_CTX-M-15 gene in a human S. Napoli isolate in Italy, and to investigate plasmid stability over time. S. Napoli 16/174478 was confirmed to be ESBL-producing. The bla_CTX-M-15 gene was shown to be located on an IncI1α plasmid of 90,272 bp (50.03 GC%) encoding for 107 coding sequences (CDS). The plasmid was successfully transferred by conjugation to an E. coli 1816 recipient strain (conjugation frequency 3.9 × 10⁻² transconjugants per donor). Transconjugants were confirmed to carry the IncI1α plasmid, and to be ESBL-producing strains as well. Moreover, transconjugant colonies maintained the plasmid for up to 10 passages. The identification of S. Napoli isolates able to produce ESBLs is of great concern, as this pathogen is frequently associated with invasive infections and a higher risk of bacteraemia, and its reservoir has not yet been clearly identified.