High-dose antibiotic-loaded acrylic cement (ALAC) is used for managing periprosthetic joint infections (PJIs). The marked increase in resistant high-virulence bacteria is drawing the attention of physicians towards alternative antimicrobial formulations to the routinely used antibiotics. To date, few studies simultaneously investigated the elution properties of a broad range of antibiotics. The aim of thepresent All the ALAC samples showed a burst release of antibiotics in the first hour, progressively decreasing overtime, and elution curves strictly adhered to a non-linear regression analysis formula. Among aminoglycosides, commonly addressed as the most appropriate antibiotics to be loaded into the bone cement, the highest elution rate was that of tobramycin. Among the glycopeptides, commonly used to treat PJIs because of the prevalence of aminoglycoside resistance, vancomycin showed better elution in comparison with teicoplanin. Clindamycin, that can be associated with aminoglycosides to prepare ALACsshowed the highest absolute and relative elutions among all the tested formulations. A noticeable elution was also detected for colistin, an antibiotic of last resort for treating multi-drug resistant bacteria. The current study demonstrates theoretical advantages in the preparation of ALAC for some antibiotics notroutinely used in the clinical setting for PJIs. The use of these antibiotics based on the infecting bacteria sensitivity may represent an useful option for physicians to eradicate PJIs.