Aseptic loosening is the most common reason for the long-term revision of cemented arthroplasties with fracture of the cement being a postulated cause or contributing factor. In our previous studies we showed that adding an antibiotic to a polymethylmethacrylate (PMMA) bone cement led to detrimental effects on various mechanical properties of the cement such as bending strength, compressive strength and fracture toughness (KIC). This finding implied that the mechanical failure of antibiotic-loaded PMMA bone cement was influenced by its pore volume fraction. Up to now this aspect has not been studied. Hence the purposes of this study were to determine (1) the influence of antibiotic (telavancin) loading on the KIC of a widely used PMMA bone cement brand (Palacos®R) and (2) the influence of pore size and pore distribution on the fracture behavior of the KIC specimens. For (2) both experimental and numerical methods (extended finite element method [XFEM]) were used allowing a comparison between the two sets of results. We found that: (1) KIC decreased with increased porosity with the drop (relative to the value for the control cement) being significant when the telavancin loading was 4.8 wt/wt % (2 g of telavancin added to 40 g of control cement powder); (2) there was a critical pore size above which there was a significant decrease in KIC and is 1 mm; (3) crack propagation was strongly influenced by pore size and pore locations (pore–pore interactions); and, (4) there was good agreement between the experimental and XFEM results. The implications of these findings for the use of a telavancin-loaded PMMA bone cement in cemented total joint arthroplasties are commented upon.