Infection continues to be a problematic complication of fracture treatment, particularly in severe open fractures. The implant design and material as well as implantation technique play an important role in the pathogenesis of local infection. The aim of our study was to determine if the local resistance to infection of a cannulated IM nail is less than that of a solid nail and more similar to that of a hollow nail. In 65 female White Zealand rabbits, the intramedullary cavity was inoculated with matching concentrations of Staphylococcus aureus, and one of the three nails was inserted. The solid nail had a greater than twofold higher resistance to infection (23%) compared to that of the other two nails (hollow, 65%; cannulated, 61%) which was statistically significant (p <0.2). No difference in infection resistance was detected between the hollow slotted and cannulated nail designs (p = 1). Although these experimental results may be clinically considered, direct extrapolation to clinical infection rates is ill advised.