Ciprofloxacin (CFX) implants containing poly(D,L-lactide) and calcium phosphates (tricalcium phosphate and hydroxyapatite) was evaluated in 50 rabbits in an experimental osteomyelitis model. Their femoral cavity was inoculated with Staphylococcus aureus. After 2 weeks, the infected focus was cleaned out and the delivery system implanted. The infection and subsequent response to treatment were evaluated by microbiological analysis, biochemical and hematological markers, body weight, temperature, clinical signs, X-rays, and histology. Infected bone cultures, treated with CFX implants, showed reduced bacterial growth against controls. All CFX was released within 6 weeks. All animals recovered within 4 weeks. Even 12 weeks after implantation, no recurrence of infection was observed. Serum C-reactive protein, platelet, and leukocyte levels increased in all animals before treatment, and 4 weeks after it were maintained or rose in control animals, while decreased to normal levels in treated ones. Body weight was characterized by pretreatment losses, then gains during recuperation, or further loss in untreated animals; with no significant intraindividual differences in body temperature. Body weight, leucocytes, platelets, and C-reactive protein turned out to be highly useful markers for monitoring this kind of infection and its treatment. CFX implants demonstrated to be an effective therapy for S. aureus bone infection. Their efficacy was also reflected in decreasing severity of clinical signs, nonprogress of radiological signs indicative of infection, and good integration into bone structure. Histological examination revealed repair, with new bone formation extending into implants.