Periprosthetic joint infection (PJI) − the most common cause of knee arthroplasty failure – may result from Gram-positive (GP) or Gram-negative (GN) bacterial infections. The question as to whether PJI due to GP or GN bacteria can lead to different rates of aseptic loosening after reimplantation remains open. We sought to investigate this issue in a retrospective review of prospectively collected data obtained from 320 patients with bacterial PJI. The results revealed that, compared with GP infections, GN infections were associated with an increased risk of aseptic loosening. In order to shed more light on this phenomenon, mice underwent intrafemoral injection of lipopolysaccharide (LPS) from GN bacteria or lipoteichoic acid (LTA) from GP bacteria. We demonstrate that LPS – but not LTA – reduced both the number of trabeculae and bone mineral density. In addition, LPS-treated mice exhibited a reduced body weight, higher serum osteocalcin levels, and an increased number of osteoclasts. LPS accelerated monocyte differentiation into osteoclast-like cells, whereas LTA did not. Finally, ibudilast – a toll-like receptor (TLR)-4 antagonist – was found to inhibit LPS-induced bone loss and osteoclast activation in mice. Taken together, our data indicate that PJI caused by GN bacteria portends a higher risk of aseptic loosening after reimplantation – mainly because of LPS-mediated effects on osteoclast differentiation. On the other hand, recent research demonstrates that thyroid stimulating hormone (TSH) reduces osteoclastogenesis by TSH receptor G-protein-coupled receptor. Therefore, our next ongoing research is to explore the regulatory relationship between thyroid-stimulating hormone, TLR4, and osteoclast activation. Our findings may pave the way towards the development of new therapeutic strategies for PJI.