Fracture-related infection (FRI) is a major complication in surgically fixed fractures. Instability of the fracture after fixation is considered a risk factor for infection; however, few experimental data are available confirming this belief. To study whether stable fractures led to higher infection clearance, mouse femoral osteotomies were fixed with either stable or unstable fixation and the surgical site was contaminated with eitherStaphylococcus epidermidis(S. epidermidis)orStaphylococcus aureus(S. aureus)clinical isolates. Infection progression was assessed at different time points by quantitative bacteriology, total cell counts in spleen and lymph node and histological analysis. Operated, non-inoculated mice were used as controls. Two inbred mouse strains (C57BL/6 and BALB/c) were included in the study to determine the influence of different host background in the outcome.Stable fixation allowed a higher proportion of C57BL/6 mice to clearS. epidermidisinoculation in comparison to unstable fixation. No difference associated with fixation type was observed for BALB/c mice. Inoculation withS. aureusresulted in a more severe infection for both stable and unstable fractures in both mouse strains; however, significant osteolysis around the screws rendered the stable group functionally unstable.Our results suggested that fracture stability could have an influence onS. epidermidisinfection, although host factors also played a role. No differences were observed when usingS. aureus, due to a more severe infection, leading to osteolysis and loss of stability in both groups. Further studies are required in order to address the biological features underlying the differences observed.