The penetration characteristics of cefazolin and cephradine in human bone were determined in 35 patients undergoing total knee replacement. The results were compared to previously reported data on patients undergoing total hip replacement. The time required to achieve peak bone levels in total knee replacement was less than in total hip replacement. Importantly, peak bone levels in total knee replacement (cefazolin: 11 mg/kg; cephradine: 7 mg/kg) were significantly less (less than or equal to 50%) than bone levels in total hip replacement (cefazolin: 30 mg/kg; cephradine: 23 mg/kg). The bone half-lives (t 1/2) of cephalosporins were prolonged in total knee replacement compared to total hip replacement because of the tourniquet effect. The reduction in peak bone levels and the bone t 1/2 of cephalosporins should be taken into account in patients receiving prophylaxis for total knee replacement. Therefore, patients undergoing total knee replacement should receive 2 g of a parenteral cephalosporin 30 min prior to surgery in order to achieve the same degree of protection, i. e., peak bone levels, as is achieved with 1 g of a cephalosporin administered prophylactically to patients undergoing total hip replacement. If the critical effect of the tourniquet is not taken into account in antibiotic prophylaxis for patients undergoing total knee replacement, then suboptimal bone cephalosporin levels may result.