BACKGROUND Patients with periprosthetic joint infection (PJI) undergoing 2-stage exchange arthroplasty may undergo an interim spacer exchange for a variety of reasons including mechanical failure of spacer or persistence of infection. The objective of this study is to understand the risk factors and outcomes of patients who undergo spacer exchange during the course of a planned 2-stage exchange arthroplasty. METHODS Our institutional database was used to identify 533 patients who underwent a 2-stage exchange arthroplasty for PJI, including 90 patients with a spacer exchange, from 2000 to 2017. A retrospective review was performed to extract relevant clinical information. Treatment outcomes included (1) progression to reimplantation and (2) treatment success as defined by a Delphi-based criterion. Both univariate and multivariate Cox regression models were performed to investigate whether spacer exchange was associated with failure. Additionally, a propensity score analysis was performed based on a 1:2 match. RESULTS A spacer exchange was required in 16.9%. Patients who underwent spacer exchanges had a higher body mass index (P < .001), rheumatoid arthritis (P = .018), and were more likely to have PJI caused by resistant (0.048) and polymicrobial organisms (P = .007). Patients undergoing a spacer exchange demonstrated lower survivorship and an increased risk of failure in the multivariate and propensity score matched analysis compared to patients who did not require a spacer exchange. CONCLUSIONS Despite an additional load of local antibiotics and repeat debridement, patients who underwent a spacer exchange demonstrated poor outcomes, including failure to undergo reimplantation and twice the failure rate. The findings of this study may need to be borne in mind when managing patients who require spacer exchange.