Emergence of Pseudomonas aeruginosa resistant to antibiotic monotherapy is one of the causes of therapeutic failure in chronic P. aeruginosa osteomyelitis. We report 15 cases of chronic (> 3 months of evolution) biopsy culture proven P. aeruginosa osteomyelitis included in an open prospective study evaluating the efficacy of prolonged treatment (> 4 months) with two effective antibiotics in combination. Mean post-treatment follow-up was 38 months. A regimen of cefsulodin in combination with oral ofloxacin was used for six patients, cefsulodin-pefloxacin for three patients, cefsulodin-ciprofloxacin for one patient, piperacillin-pefloxacin for one patient, cefsulodin-fosfomycin for one patient, imipenem-ciprofloxacin for two patients and amoxicillin-ciprofloxacin-fosfomycin for one patient as home therapy. The clinical cure rate of 73% and bacteriological cure rate of 93% are far superior to those previously described in the literature. We did not observe adverse drug reactions. We think that a prolonged use of two effective antibiotics in combination is a safe and improved therapeutic schedule for chronic P. aeruginosa osteomyelitis.