Introduction <p>Debridement, antibiotics, and implant retention (DAIR) is a commonly employed strategy for managing acute postoperative prosthetic joint infections (PJI) while preserving the prosthesis. However, the clinical value of an unplanned second DAIR - performed due to inadequate infection control - remains controversial and is often considered a potential treatment failure. This study aimed to compare the two year clinical outcomes of patients undergoing a single DAIR versus those requiring an unplanned second DAIR for acute postoperative PJI of the hip or knee.</p> Methods <p>We retrospectively reviewed electronic medical records of patients treated with DAIR for acute postoperative PJI between January 1999 and December 2020. Patients were categorized into two groups: those managed with a single DAIR (DAIR-1 group) and those requiring an unplanned second DAIR within 12 weeks (DAIR-2 group). Treatment failure was defined as any of the following: further debridement beyond 12 weeks, revision surgery with prosthesis removal, initiation of long-term suppressive antibiotic therapy, or PJI-related mortality. Patients lost to follow-up before two years were excluded.</p> Results <p>A total of 318 patients were included, with 292 in the DAIR-1 group and 26 in the DAIR-2 group. Mean follow-up was 89.4 months. At two years, revision surgery was required in 19.2% (56/292) of DAIR-1 patients and 42.3% (11/26) of DAIR-2 patients (<i>p</i> = 0.005). Overall failure-free survival at two years was observed in 75.3% (220/292) of DAIR-1 patients compared to 46.2% (12/26) of those in the DAIR-2 group (<i>p</i> = 0.001).</p> Conclusion <p>Unplanned second DAIR procedures are associated with significantly lower success rates at two years. Nonetheless, given that nearly half of these patients remained free of failure, a second DAIR may still be a reasonable therapeutic option in selected cases, provided that the increased risk of a poorer prognosis is taken into account.</p>