Discovered in 1949, the antibiotic colistin was initially used for therapeutic purposes. Parenteral use of colistin was gradually abandoned because of its side-effect profile, especially its nephrotoxicity and neurotoxicity. Despite the risk of these potentially serious adverse effects, increasing resistance of Gram-negative bacteria has led to a renaissance of intravenous use of colistin in the last few years. Local administration of colistin is an alternative method to minimise the risk of systemic toxicity. We present a case of extensively drug-resistant Pseudomonas aeruginosa osteomyelitis treated successfully with high-dose colistin- and tobramycin-impregnated bone cement as a drug delivery vehicle. For the first time, local colistin concentrations in drainage and synovial fluid were quantified in order to determine the optimal dose and to minimise serious side effects. Insertion of a bone cement spacer loaded with a high dose of tobramycin and colistin resulted in local colistin levels at the infection site that exceeded the minimum inhibitory concentration (MIC) of colistin against the isolated P. aeruginosa five-fold on Day 4. Thus, the treatment may be expected to exert a prolonged effect. Whereas systemic administration of colistin alone was not sufficient to treat the infection, combined local and parenteral therapy led to eradication of P. aeruginosa in this patient. Plasma colistin levels remained in the therapeutic range, which confirms the systemic safety of the method.