Abstract Background Elective implant removal (IR) after fracture fixation is one of the most common procedures within (orthopedic) trauma surgery. The rate of surgical site infections (SSIs) in this procedure is quite high, especially below the level of the knee. Antibiotic prophylaxis is not routinely prescribed, even though it has proved to lower SSI rates in other (orthopedic) trauma surgical procedures. The primary objective is to study the effectiveness of a single intravenous dose of 2 g of cefazolin on SSIs after IR following fixation of foot, ankle and/or lower leg fractures. Methods This is a multicenter, double-blind placebo controlled trial with a superiority design, including adult patients undergoing elective implant removal after fixation of a fracture of foot, ankle, lower leg or patella. Exclusion criteria are: an active infection, current antibiotic treatment, or a medical condition contraindicating prophylaxis with cefazolin including allergy. Patients are randomized to receive a single preoperative intravenous dose of either 2 g of cefazolin or a placebo (NaCl). The primary analysis will be an intention-to-treat comparison of the proportion of patients with a SSI at 90 days after IR in both groups. Discussion If 2 g of prophylactic cefazolin proves to be both effective and cost-effective in preventing SSI, this would have implications for current guidelines. Combined with the high infection rate of IR which previous studies have shown, it would be sufficiently substantiated for guidelines to suggest protocolled use of prophylactic antibiotics in IR of foot, ankle, lower leg or patella. Trial registration Nederlands Trial Register (NTR): NL8284, registered on 9th of January 2020, https://www.trialregister.nl/trial/8284