We investigated the diffusion of penicillin-G, cloxacillin, clindamycin, and netilmicin into synovial fluid and membrane in rabbits. Purulent arthritis was induced in the right knee of each rabbit by inoculation of Staphylococcus aureus phage type 3C, whereas sterile saline was injected into the left knee to serve as a control. Two days later, concentrations of antibiotics were determined in serum, synovial fluid, and membrane after an intramuscular single dose. All four drugs diffused readily into infected joints, whereas the corresponding concentrations in the normal joints were 2-3 times lower. Clindamycin showed the highest intraarticular penetration, cloxacillin the lowest. The lower penetration of cloxacillin corresponded to its higher protein binding in rabbit serum. Considering the sufficient local concentrations achieved, parenteral treatment obviates the need for local instillation of these antibiotics.