Chronic periprosthetic infection is one of the most feared and difficult to treat complications of total joint arthroplasty1-3. Although treatment is controversial, a two-stage revision with interim placement of an antibiotic-impregnated polymethylmethacrylate (PMMA) spacer is considered the so-called “gold standard4-6.” Vancomycin and tobramycin are two of the most common antibiotics admixed with PMMA. Spacers with this combination of antibiotics have been demonstrated to elute bactericidal concentrations of antibiotics locally7-10. While systemic concentrations of antibiotic used in this technique are generally low8,9,11-13, several factors can lead to high serum concentrations, including the amount of antibiotic implanted14, combining vancomycin and an aminoglycoside10,15, and manual mixing, which causes variation in elution pharmacodynamics15. Both vancomycin and tobramycin have been associated with renal failure when used systemically in 13.5% (thirty-nine of 289) and 12.9% (275 of 2130) of cases, respectively16,17; there is a synergistic effect when both are used concurrently18,19. To the best of our knowledge, although previous series have not demonstrated nephrotoxicity when these antibiotics were used in PMMA spacers8,13-15,20, previous case reports have21-24. In this report, we present two cases of nephrotoxicity and elevated serum tobramycin levels that developed after the implantation of a PMMA spacer with high doses of vancomycin and tobramycin. Improvement in renal function occurred following removal of the spacers. Both patients were informed that data concerning their cases would be submitted for publication, and they provided consent. Case 1. A seventy-seven-year-old woman with a history of hypertension, gout, a seizure disorder, and a right total knee arthroplasty presented to our …