Aim and hypothesis <p>To compare antibiotic prophylaxis with a single or multiple doses in total knee arthroplasty surgery. To assess whether the use of a multiple dose is justified in routine clinical practice. The starting hypothesis is that the use of multiple doses of prophylactic antibiotics does not reduce surgical infection and may increase costs, hospital stay and antibiotic resistance. </p> Methods <p>A systematic review and meta-analysis of the literature was carried out following the PRISMA guidelines. The search was carried out on 5 April 2024 in the PubMed and Cochrane Library databases by entering the terms: (antibiotic prophylaxis) AND ((total knee arthroplasty) OR (knee prosthesis)) and the Joanna Briggs Institute quality assessment tool was used to evaluate the quality of the included studies.</p> Results <p>Four articles have been included, all of which are retrospective cohort studies comparing the use of single-dose antibiotic prophylaxis with multiple-dose prophylaxis in total knee arthroplasty. No significant differences have been observed in terms of postsurgical infection rate between single- and multiple-dose prophylaxes.</p> Conclusions <p>The use of multiple-dose antibiotic prophylaxis in total knee arthroplasty has not been shown to reduce infections or other complications compared to single-dose antibiotic prophylaxis. No evidence has been found to justify the use of multiple-dose antibiotic prophylaxis in knee arthroplasty surgery.</p>