Objective To evaluate the clinical efficacy of a rapid 3D-printed patient-specific osteotomy guide in knee replacement surgery， and provide guidance for its widespread clinical application. Methods A total of 80 patients with end-stage knee osteoarthritis who had undergone Total Knee Arthroplasty （TKA） were selected and randomly divided into two groups. The first group comprised 40 cases （40 knees） that underwent traditional TKA， while the second group consisted of 40 patients （40 knees） in the 3D-printed osteotomy guide group. Various parameters， including surgery duration， intraoperative blood loss， time to ambulation after surgery， mechanical axis angle between femur and tibia post-surgery， Visual Analog Scale （VAS） score， Hospital for Special Surgery （HSS） knee score， Western Ontario and McMaster Universities Osteoarthritis Index （WOMAC） score， range of motion （ROM） of the knee， and other indicators were analyzed separately for both groups. Statistical analyses were conducted. Results All the patients underwent surgery smoothly and were followed up for 3 ~ 12 months. In comparison to the traditional osteotomy guide group， the 3D-printed osteotomy guide group demonstrated significantly shorter surgery duration （P < 0.05）， reduced intraoperative blood loss， earlier time to first ambulation after surgery （P < 0.05）， lower postoperative VAS score， and smaller mechanical axis angle between the femur and tibia after surgery （P < 0.01）. At 6 months post-surgery， both groups showed significantly improved KSS scores compared to preoperative values （P < 0.01）. The KSS score of the 3D-printed guide group was higher than that of the traditional surgical guide group at 6 months after surgery （P < 0.05）， but there was no statistical difference in KSS scores between the two groups （P > 0.05）. WOMAC scores for both groups decreased over time at 3 and 6 months post-surgery compared to preoperative scores （P < 0.05）. At these time points， WOMAC scores were lower in the 3D-printed guide group than in the traditional osteotomy guide group （P < 0.05）. One case of hematocele and infection occurred in the traditional osteotomy guide group； however， successful discharge was achieved following re-debridement while preserving the prosthesis. None of the surgical patients experienced complications such as neurovascular injury， deep vein thrombosis， prosthesis loosening or periprosthetic fractures. Conclusion Compared to conventional total knee arthroplasty （TKA） surgery， the utilization of a rapid 3D-printed osteotomy guide for knee replacement presents several advantages， including reduced surgical operation duration， minimal intraoperative blood loss， precise and expeditious osteotomies， accelerated postoperative recovery， and heightened patient satisfaction during medical consultations. Notably， its clinical efficacy surpasses that of traditional approaches.