Introduction. Calcium sulphate is a resorbable void filler that can be used for local antibiotic delivery. Results from clinical studies on chronic osteomyelitis thus treated with local vancomycin have already been published. Despite significant exposure to this drug, there are no pharmacokinetic studies published so far. Based on observations in our patients, a model predicting vancomycin serum and wound fluid levels and toxicity potential is presented. Methods. Following implantation of Osteoset® added with vancomycin, serum and wound fluid concentrations of this antibiotic have been monitored systematically. The pharmacokinetic analysis was performed using a non-linear mixed-effects model based on a one-compartment model with first-degree absorption. Results. Data from 43 patients treated between October 2006 and August 2010 were analysed. Serum concentrations remained far below the usually accepted trough levels of 10 mg/L, and were still acceptable in two cases of post-operative renal failure. Wound fluid concentrations around 1,000 mg/l were observed for the first 7–10 days, and remained above usual minimal inhibitory concentrations for approximately a month. Discussion and Conclusion. This is the first pharmacokinetic exploration of calcium sulphate added with vancomycin for local antibiotic therapy. The systemic exposure to vancomycin is low and appears safe even after implantation of up to 6 g vancomycin, except in case of markedly impaired renal function. Wound fluid concentrations of vancomycin appear extremely interesting for further studies