The rate of peri-prosthetic infection following total joint replacement continues to rise, and attempts to curb this trend have included the use of antibiotic-loaded bone cement at the time of primary surgery. We have investigated the clinical- and cost-effectiveness of the use of antibiotic-loaded cement for primary total knee replacement (TKR) by comparing the rate of infection in 3048 TKRs performed without loaded cement over a three-year period versus the incidence of infection after 4830 TKRs performed with tobramycin-loaded cement over a later period of time of a similar duration. In order to adjust for confounding factors, the rate of infection in 3347 and 4702 uncemented total hip replacements (THR) performed during the same time periods, respectively, was also examined. There were no significant differences in the characteristics of the patients in the different cohorts. The absolute rate of infection increased when antibiotic-loaded cement was used in TKR. However, this rate of increase was less than the rate of increase in infection following uncemented THR during the same period. If the rise in the rate of infection observed in THR were extrapolated to the TKR cohort, 18 additional cases of infection would have been expected to occur in the cohort receiving antibiotic-loaded cement, compared with the number observed. Depending on the type of antibiotic-loaded cement that is used, its cost in all primary TKRs ranges between USD $2112.72 and USD $112 606.67 per case of infection that is prevented.