Background: The use of antibiotic-loaded cement is believed to prevent infection in primary total knee arthroplasty, but there is a lack of randomized studies to support this concept. The aim of this study was to evaluate the use of an antibioticloaded cement to reduce the infection rate in primary total knee arthroplasty. Methods: This is a prospective randomized study with 2948 cemented total knee arthroplasties, in which bone cement without antibiotic was used in 1465 knees (the control group) and a bone cement loaded with erythromycin and colistin was used in 1483 knees (the study group). All patients received the same systemic prophylactic antibiotics. The patients were followed for a minimum of twelve months. The rate of infection was analyzed according to the criteria of the Centers for Disease Control and Prevention. Results: The rate of deep infection (1.4% in the control group and 1.35% in the study group; p = 0.96) and the rate of superficial infection (1.2% and 1.8%, respectively; p = 0.53) were similar in both groups. The factors related to a higher rate of deep infection in a multivariate analysis were male sex and an operating time of >125 minutes. Conclusions: The use of erythromycin and colistin-loaded bone cement in total knee arthroplasty did not lead to a decrease in the rate of infection when systemic prophylactic antibiotics were used, a finding that suggests that the use of antibiotic-loaded bone cement would not be indicated in the general population. Further research is needed to assess whether its use is recommended for patients with a higher risk of infection. Level of Evidence: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence. COPYRIGHT © 2013 BY THE JOURNAL OF BONE AND JOINT SURGERY, INCORPORATED.