Background <p>Periprosthetic joint infection (PJI) poses a formidable challenge following total joint arthroplasty (TJA). Whether using Debridement, Antibiotics, and Implant Retention (DAIR) for acute cases or one/two-stage revision for chronic scenarios, postoperative antibiotics administered intravenously is standard. However, this delivery method inevitably risks hepatic and renal function impairment, lacking a sufficiently minimal biofilm eradication concentration. Intra-articular infusion as a novel antibiotic delivery method can circumvent systemic circulation, reduce the risk of hepatic and renal function impairment, and provide a sufficiently high antibiotic concentration at the prosthetic infection site. Yet, the efficacy of these methods has never been evaluated in a randomized controlled trial. The study aims to investigate infection control rates within 2 years post intra-articular antibiotic infusion versus intravenous antibiotic administration in a randomized design.</p> Methods <p>This pragmatic, multicenter, two-armed, parallel group, open, randomized non-inferiority trial (non-inferiority margin—15%) involves 11 high-volume tertiary referral centers (1:1 allocation). One hundred forty-two eligible PJI patients following total knee arthroplasty, undergoing one-stage revision, were randomly assigned to intra-articular or intravenous antibiotics. Blinding is not possible due to the nature of the intervention. However, data collectors and statistical analysts remain blind to the groups. All patients will be followed up for 2 years. The primary outcome is the infection control rate, and the secondary outcomes include functional outcome, concentrations of antibiotics in peripheral blood and joint fluid, along with liver and kidney injury, the reoperation rate, and antibiotic usage for both patient groups.</p> Discussion <p>This is the first randomized controlled trial to compare the efficacy of intra-articular antibiotic infusions and intravenous antibiotic administration. If intra-articular antibiotic infusion demonstrates non-inferiority in infection control rate compared to traditional intravenous antibiotic administration, with lower rates of hepatic and renal impairment, fewer complications, and reduced antibiotic usage, then this mode of drug administration should be further advocated in the treatment of periprosthetic knee infections. The results of the trial will benefit patients, clinicians, and overall healthcare resource utilization.</p> Trial registration <p>The randomized trial is registered on <a href="https://www.chictr.org.cn/showproj.html?proj=36750">https://www.chictr.org.cn/showproj.html?proj=36750</a> with ID ChiCTR1900022102, initial release date March 25, 2019.</p>