The in vitro elution of penicillin and gentamicin from polymethylmethacrylate was studied qualitatively and quantitatively. Penicillin eluted poorly from Simplex P. Higher levels of penicillin eluted in sustained fashion from Palacos; concentrations of one microgram or more per gram of cement were recorded during the thirteen weeks of observation. Although the in vitro leaching of gentamicin from Palacos cement was similar to that of penicillin, there were two important differences: (1) most of the gentamicin leaching from the Palacos did so within the first twenty-four hours, and (2) the concentrations decreased to less than one microgram per gram of cement after the sixth week of observation. The in vivo elutions of penicillin and gentamicin from Palacos were studied in canine femora. The concentrations of penicillin and gentamicin in the endosteal bone at the bone-cement interface exceeded the concentrations found after intravenous administration of either agent. Bactericidal concentrations of gentamicin in osseous tissue persisted for seven months after implantation. Peak concentrations in serum following the depot administration of either penicillin or gentamicin occurred within thirty minutes of implantation. Concentrations of gentamicin in serum did not approach toxic levels. These data suggest that a high concentration of either penicillin or gentamicin can be obtained at the bone-cement interface--one of the vulnerable sites in total joint arthroplasty--for a prolonged period with the depot administration of these agents in acrylic bone cement. These osseous concentrations can be achieved without exposing the patient to elevated levels in serum and their potential toxic side effects.