High-dose antibiotic-loaded bone cement (ALBC) spacers are commonly used to treat prosthetic joint infections following total hip and knee arthroplasties. This methodology can provide high local antibiotic concentrations while minimizing systemic exposure and toxicity. The occurrence of acute kidney injury (AKI) is rarely reported. Available literature suggests that the rate may be higher than previously thought. We report a case of significant systemic tobramycin absorption with concomitant acute renal failure in a 69-year-old female following the implantation of a high-dose ALBC spacer containing both tobramycin and vancomycin. The tobramycin level 24 h post-surgery was 5.8 mcg/mL. Due to concomitant renal failure, antibiotic clearance was poor and resulted in prolonged exposure to elevated aminoglycoside levels. Recovery of renal function occurred, but clinicians should be vigilant in considering the potential impact ALBC spacers can have on post-operative renal function if antibiotic elution is higher than expected.