Abstract: Background: Prior studies have indicated that administration of prolonged courses of oral antibiotics after Stage 2 reimplantation surgery for periprosthetic joint infection (PJI) results in a lower rate of recurrent PJI. However, there is concern that this antibiotic usage results in an increased risk of antibiotic resistance in any subsequent PJI that does occur. Methods: We retrospectively reviewed patients who underwent Stage 2 reimplantation surgery for PJI within the national Veterans Affairs hospital system of the United States. We compared those who received at least 2 weeks of oral antibiotics after Stage 2 reimplantation to those who did not. The primary outcome was the proportion of organisms resistant to four classes of antibiotics (tetracyclines, fluoroquinolones, oral beta-lactams, and sulfonamides) in recurrent PJI. Secondary outcomes included recurrent PJI and death. Results: Of the 605 patients who underwent Stage 2 reimplantation for PJI, 154 patients received at least 14 d of antibiotics after surgery and 451 patients did not. Bacteria causing recurrent PJI in patients who received prolonged antibiotics were more likely to be resistant to tetracyclines and trimethoprim-sulfamethoxazole but not oral beta-lactams or fluoroquinolones. There was no difference in risk of recurrent PJI or death between the two groups. Conclusions: Prolonged oral antibiotic treatment after Stage 2 reimplantation increases the risk of antibiotic resistance to some antibiotics in subsequent PJI. We recommend further research to identify the best choice of antibiotic and duration after Stage 2 reimplantation, to maximize benefits while minimizing risks.