The purpose of this study was to assess the systemic safety and potential adverse effects of using a high-dose antibiotic-impregnated cement spacer after resection arthroplasty of an infected total knee replacement. Between October 2000 and December 2002, 36 knees (34 patients) had a resection arthroplasty of an infected total knee prosthesis with placement of a high-dose antibiotic impregnated cement spacer. There were 24 men and 10 women with a mean age of 66.5 years (range, 48-84 years). All spacers placed contained an average of 3.4 batches of cement with an average total dose of 10.5 g of vancomycin (range, 3-16 g) and 12.5 g of gentamicin (range, 3.6-19.2 g). All patients were followed up post-operatively until reimplantation for evidence of renal failure. The preoperative creatinine ranged from 0.7 to 1.8 mg/dL. All patients were concomitantly treated with 6 weeks of intravenous organism-specific antibiotics. One patient with normal preoperative renal function (Cr 0.7 mg/dL) had a perioperative 1-day transient rise in serum creatinine (1.7 mg/dL) postoperatively that subsequently normalized. No patients showed any clinical evidence of acute renal insufficiency, failure, or other systemic side effects of the antibiotics. Treatment of patients with an infected total knee arthroplasty with high-dose vancomycin and gentamicin antibiotic spacers seems to be clinically safe.