Silver is used extensively in both hospitals and outpatient clinics as a disinfectant coating agent on various devices. Resistance to silver was recently reported as an emerging problem inEnterobacteriaceae.Multidrug-resistant high-risk clones ofKlebsiella pneumoniaeare common causes of serious healthcare-associated infections worldwide posing a serious threat to patients. In this study, we investigated the capacity of both high-risk (CG14/15 and CG258) and minor clone strains ofK. pneumoniaeto develop resistance to silver. Resistance was inducedin vitroin silver-susceptible but otherwise multidrug-resistant clinical isolates. Genetic alterations in the silver-resistant derivative strains with regard to the silver-susceptible isolates were investigated by whole-genome sequencing. The transferability of high-level resistance to silver was also tested. We demonstrated that the high-level resistance to silver can quickly evolve as a consequence of a single-point mutation either in thecusS gene of the chromosomally encoded CusCFBARS efflux system and/or in thesilS gene of the plasmid-encoded Copper Homeostasis and Silver Resistance Island (CHASRI) coding also for a metallic efflux. The minimal inhibitory concentrations (MICs) of the strains increased from 4 mg/L (23.5 μM) AgNO3to >8,500 mg/L (>50,000 μM) AgNO3during induction. Harboring the CHASRI proved an important selective asset forK. pneumoniaewhen exposed to silver. Successful conjugation experiments usingEscherichia coliK12 J5-3Rifas recipient showed that high-level silver resistance can transmit between strains of high-risk clones ofK. pneumoniae(ST15 and ST11) and isolates from additional species ofEnterobacteriaceae. The lack of fitness cost associated with the carriage of the CHASRI in a silver-free environment and the presence of the RelEB toxin–antitoxin system on the conjugative plasmids could advance the dissemination of silver resistance. Our results show that multidrug-resistant high-risk clones ofK. pneumoniaeare capable of evolving and transmitting high-level resistance to silver. This observation should warrant a more judicious use of silver coated-devices to prevent the extensive dissemination of silver resistance.