Objective To explore the clinical and epidemiological characteristics of fosfomycin (FOS)-resistant hypervirulent carbapenem-resistant Klebsiella pneumoniae (hv-CRKP) strains, as well as potential molecular mechanisms of FOS resistance, and provide reference for clinical anti-infection treatment decision making. Methods Through antimicrobial susceptibility testing, non-repetitive hv-CRKP strains from a tertiary first-class hospital from January to December 2023 were screened and collected. The clinical characteristics and antimicrobial resistance were analyzed, and the molecular epidemiological characteristics of FOS non-susceptible hv-CRKP was studied by whole genome sequencing. Results A total of 73 hv-CRKP strains were included in the analysis, out of which 34 strains (46.6%) were resistant to FOS. The incidence of diabetes mellitus in patients in the FOS non-susceptible group was higher than that in the FOS susceptible group (P<0.05). There was no statistically significant difference among other clinical characteristics. Antimicrobial susceptibility results showed that, except for tigecycline, colistin, ceftazidime /avibactam, and FOS, the resistance rates of hv-CRKP to other common antimicrobial agents were all >90%. The detection of capsule serotypes and virulence genes showed that all hv-CRKP were Klebsiella pneumoniae carbapenemase (KPC)-producing ST11 strains, with the main serotypes being KL64 (47.9%) and KL25 (52.1%). There was no statistically significant difference in distribution of hv-CRKP capsule serotype between the FOS susceptible and FOS non-susceptible groups. Resistance gene detection results showed that the carbapenem-resistance gene bla_KPC as well as FOS resistance genes fosA and fosA6 were widely presented in hv-CRKP, with only one strain carrying the fosA3 gene detected in the FOS non-susceptible group. All 73 hv-CRKP strains carried the Leu359Gln mutation modification in murA, and some had mutations in the transport system-related gene glpT. No other FOS modification enzyme resistance genes were detected, such as fosA2, fosA5, fosA10, fosB, fosC, and fosX. Conclusion hv-CRKP has a high resistance rate to FOS. Modification mutations in murA and glpT, as well as the wide presence of FOS resistance genes fosA and fosA6 are the main mechanisms of FOS resistance in this study. It should be noted that fosA gene may be captured by strong promoters-containing high copy plasmids, leading to FOS resistance.