Prolonged prosthetic life span is a goal that orthopedic surgeons are pursuing. Both septic and aseptic loosening may lead to prosthetic failure. For decades, antibiotics have been applied in arthroplasty to prevent septic loosening, with excellent clinical results, although few therapies have been able to prevent aseptic loosening. Research on aseptic loosening indicates that osteoclasts play an essential role in this process. Thus, the exploration of osteoclastogenesis inhibitor has become of interest. Erythromycin is a broad-spectrum antimicrobial that has been used to prevent postoperative infection after artificial joint replacement. A new function to inhibit particle-induced osteolysis has been discovered recently. Fundamental research indicates that erythromycin administration should be an excellent method for the prophylaxis of prosthetic failure and should increase the life span of artificial joint in clinics.