Antibiotic-loaded PMMA spacers are used with increased frequency in two-stage revision arthroplasty. The release of aminoglycosides and vancomycin, the most commonly used antibiotics, is prompt, and concentrations are inhibitory. The release kinetic from PMMA bone cement shows a biphasic profile, consisting in an initially high and rapid drug release followed by a slower but sustained phase. However, this general profile of drug release kinetics from PMMA spacers in vitro may have great variability in terms of drug amount, modality, and duration of elution. Initial drug concentration, cement surface area and porosity are essential and well-known factors in determining the drug release. Moreover, viscosity, vacuum-preparation and the different technical characteristics of commercially available spacers are additional factors of variability. Industrial preformed spacers are considered superior to custom-made devices because of uniform mixing and standardized procedures. Spacers produced by different manufacturers vary in their mechanical properties and antibiotic elution characteristics. Small changes in the formulation of a bone cement can also affect these properties. Similar bone cements produced by various brands release different amount of drugs. Gentamicin diffuses from Palacos in a larger amount and for a longer period than from Simplex and CMV. Spacers produced in France (Synicem™) and in Argentina (Subiton™) elute less total amount of gentamicin than those produced in Italy (Spacer G™) and show a delayed peak drug release. The low initial release of antibiotic can contribute to unsatisfactory antimicrobial effect and to the risk of selection of resistant bacteria. Some spacers release gentamicin for longtime (months), while others release antibiotic for only two weeks. In the last years an evolution of PMMA spacers production occurred and modifications in the polimerization process of cement can increase cement porosity and antibiotic elution from spacers. The current commercial preformed spacers for 10 days elution (Spacer G™, prepared with Cemex HP) release more gentamicin (34.1 mg) than previous models, which were prepared with Cemex SP (16.4 mg). Furthermore, they maintain a high elution rate (1.4–1.6 mg/day after one month). The combination of Gentamicin and Vancomycin mantains an elution pharmacokinetic profile that is superimposable to that of Gentamicin and Vancomycin alone, with synergistic effects against multiresistant bacteria in prosthetic infection site. In conclusion, the antibiotic release from PMMA spacers of various brands is not equivalent. The old elution data are no longer valid for new preparations. Consequently, this additional factor of variability should be considered in clinical practice and literature data utilisation.