Background Two-stage tissue expander/implant-based method has been used predominantly for breast reconstruction. Implant rupture is one of the bothersome complications, inducing additional morbidity including reoperation. The present study aimed to identify the independent factors associated with development of implant rupture. Patients and Methods Patients who underwent immediate two-stage prosthetic breast reconstruction between 2010 and 2016 were reviewed. Inserted implants were followed up using magnetic resonance imaging every 2 years and/or ultrasound/computed tomography scans every 6 or 12 months that were conducted for cancer surveillance. Associations of perioperative and intraoperative variables with the development of implant rupture were evaluated. Results In total, 797 cases (744 patients) were analyzed. During a median follow-up of 43 months after second-stage operation, implant rupture was identified in 22 cases. The 5-year cumulative incidence was 3.1%. Multivariable analyses showed that the interval between the first- and second-stage operations was inversely associated with the risk of implant rupture. Maximal discrimination was observed at the interval of 6.5 months. Cases with an interval ≤ 6 months were associated with higher risks for implant rupture than those with ≥ 7 months, after adjusting for other variables. Type of implant was associated with the development of implant rupture, showing that using two kinds of fourth-generation implant (Allergan Biocell textured round and Allergan smooth round implants) was associated with a significantly increased risk of implant rupture compared with that of Mentor MemoryShape implants (fifth-generation implant). Conclusion Several operation-related variables appear to be associated with implant rupture in two-stage prosthetic reconstruction.