Klebsiella pneumonia is a major cause of community- and hospital-acquired bacterial pneumonia. OmpA (KpOmpA) is one of the most abundant virulence factors produced by K. pneumonia. This bacterial surface protein is recognized by the host immune system as apathogen-associated molecular pattern (PAMP). We used a yeast two-hybrid assay to examine novel KpOmpA-human protein binding interactions. The major intracellular iron-storage protein, ferritin, was one of the four proteins identified. We hypothesized that the virulence mediated by KpOmpA could be at least partly due to a direct, inflammation-associated and cell cycle-arresting binding interaction between KpOmpA and the host ferritin. We confirmed the direct binding between KpOmpA and ferritin in HEp-2 cells. We also found that KpOmpAco-localized with ferritin within the perinuclear region, and enveloped the entire ferritin surface. KpOmpA treatment resulted in G2/M phase cell cycle arrest. Transcription and expression of pro-inflammatory cytokines (IL-1β, IL-6, IL-8, and TNF-α) also increased. This study revealed a novel interaction between KpOmpA and human ferritin that may have a significant role in K. pneumoniae virulence. The results indicated that KpOmpAis a potential therapeutic target for the treatment of K. pneumoniae infection.