Apart from inadequate antimicrobial treatment, specific virulence factors contribute to the high attributable mortality of infections caused by multidrug-resistant (MDR) Klebsiella pneumoniae. We explored the roles of MDR and clones as virulence determinants of K. pneumoniae and their interaction with innate immunity. Twenty isolates were studied and characterized by resistance phenotype and multilocus sequence type (MLST). Human peripheral blood mononuclear cells (PBMCs) were stimulated for the production of proinflammatory cytokines by live and heat-killed isolates and plasmid DNA; modulation by cellular pathway inhibitors was explored. Survival of 30 mice was recorded after intraperitoneal challenge with susceptible and K. pneumoniae carbapenemase (KPC)-producing isolates. Splenocytes of mice were stimulated for the production of pro- and anti-inflammatory cytokines. Isolates were divided into different patterns of production of tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β) poststimulation in relation to both the MLST clone and resistance phenotype. The sequence type 383 (ST383) clone producing Verona integron-encoded metallo-β-lactamase (VIM) stimulated high production of both TNF-α and IL-1β. Clone ST17 producing KPC elicited low TNF-α production; this was reversed by Toll-like receptor 9 (TLR9) antagonists, indicating an effect of plasmid DNA. This isolate was linked with early death of mice compared to high-TNF-α-producing isolates. We conclude that KPC-producing isolates seem to be highly virulent in a low-TNF-α-release environment, suggesting an immunoparalysis induction mechanism. KPC plasmids may directly contribute to the immune system stimulation.