A. rabbit model of Staphylococcus aureus osteomyelitis was used to compare 3 weeks of clindamycin-impregnated polymethylmethacralate (PMMA) bead treatment with 3 weeks of gentamicin-impregnated polymethylmethacralate bead treatment, 4 weeks of parenteral clindamycin treatment, and surgical debridement without any antibiotic treatment. The animals were weighed throughout the course of the experiment and cortical bone and marrow flush specimens were obtained for bacterial culture at the end of therapy. The cortical specimens were bacteria free in 100% (6/6) of the animals receiving parenteral clindamycin, 83% (5/6) of the animals in the clindamycin PMMA group and, none of the animals in the gentamicin PMMA group. The marrow flush specimens were bacteria free in 83% (5/6) of the animals in the parenteral clindamycin group, 67% (4/6) of the animals in the clindamycin PMMA group, and 40% (2/5) of the animals in the gentamicin PMMA group. While these findings are preliminary and further studies with larger numbers of animals are needed, the authors suggest that when PMMA bead therapy is being contemplated, serious consideration should be given to replacing gentamicin with clindamycin in treatment of gram-positive osteomyelitis. Furthermore, incorporation of clindamycin with gentamicin (or tobramycin) should be considered when treating mixed gram-positive and gram-negative osteomyelitis.