The aim of the present study was to investigate the local pharmacokinetic properties and the systemic safety of vancomycin-impregnated cancellous bone grafts in the treatment of spondylodiscitis. Between 2010 and 2012, 8 patients (5 females, 3 males, mean age 68.75 y.) were treated with this method. Local vancomycin concentrations reached median values of 179 µg/mL (maximum 365 µg/mL) on day 1, decreasing to 98 µg/mL on day 3. The urine vancomycin concentrations showed similar pharmacokinetic properties as those locally determined. On day 1, median values were at 28.05 µg/mL (maximum 287 µg/mL). All serum vancomycin concentrations were in all cases and on every day below <2 µg/mL. The median serum creatinine values were preoperatively 0.87 mg/dL, followed by 0.625 mg/dL, 0.705 mg/dL, and 0.835 mg/dL on day 7, 14, and 28, respectively. No cases of ototoxicity could be observed. At a mean follow-up of 16.5 [4–36] months no cases of reinfections or persistent infections could be seen. In conclusion, the implantation of vancomycin-loaded cancellous bone grafts is an effective option in the treatment of spondylodiscitis with a high infection eradication rate and no risk of any systemic toxicity. The pharmacokinetic properties can be easily monitored locally, in the urine and the serum.