Background <p>Managing periprosthetic joint infections (PJIs) in orthopedic surgery is particularly challenging, especially with two-stage exchange arthroplasty. This study examines the impact of different single spacer exchange strategies on reimplantation success, reinfection risk, and survival outcomes.</p> Methods <p>A retrospective review was conducted on 650 patients who underwent two-stage exchange arthroplasty for PJIs from 2000 to 2017. After exclusions, 94 patients with a single spacer exchange were identified. We used univariate and multivariate Cox regression analyses and propensity score matching to evaluate reimplantation success, as defined by Delphi-based criteria.</p> Results <p>Among the 94 patients, 77 underwent reimplantation surgery post-single spacer exchange. Of these, 29 had strategic spacer exchanges, and 48 had unplanned exchanges due to mechanical problems (22) or persistent infections (26). Unplanned exchanges due to persistent infections and a Charlson Comorbidity Index (CCI) over seven were significant predictors of poor reimplantation success and higher reinfection risk (<i>p</i> &lt; 0.05). Patients transferred from other hospitals, those with the same pathogen causing persistent PJI as in the first stage, and those with the same pathogen identified in unexpected positive intraoperative cultures (UPICs) had increased reinfection risks (<i>p</i> &lt; 0.05). Survival analysis indicated that unplanned exchanges due to persistent PJI significantly elevated failure rates (<i>p</i> &lt; 0.05).</p> Conclusions <p>While previous studies have suggested poor outcomes associated with spacer exchanges, our findings indicate that this is not universally the case. However, unplanned spacer exchanges, particularly those necessitated by persistent infections, result in significantly worse outcomes compared to other strategies. Therefore, unplanned exchanges require meticulous management to improve patient outcomes and reduce the risk of reinfection.</p> Level of evidence <p>III.</p>