Background: Irrigation and débridement with retention of prosthesis is commonly performed for periprosthetic joint infection. Infection control is reportedly dependent on timing of irrigation and débridement relative to the index procedure. Questions/purposes: We therefore (1) compared the ability of irrigation and débridement to control acute postoperative, acute delayed, and chronic infections and (2) determined whether any patient-related factors influenced infection control. Patients and Methods: We retrospectively reviewed the records of 136 patients (138 joints) from two institutional databases treated with irrigation and débridement between 1996 and 2007. Mean age at time of treatment was 64 years (range, 18-89 years); 77 (56%) joints were in women. Three subgroups were extracted: acute postoperative infections, occurring within 4 weeks (52 joints), acute delayed infections occurring after 4 weeks with acute onset of symptoms (50 joints), and chronic infections (36 joints). Minimum followup was 12 months (average, 54 months; range, 12-115 months). Failure to control infection was reported as the need for any subsequent surgical intervention and/or use of long-term suppressive antibiotics. Results: Infection control was not achieved in 90 joints (65%; 82 requiring return to surgery and eight remaining on long-term suppressive antibiotics). Failure rates were 69% (36 of 52), 56% (28 of 50), and 72% (26 of 36) for acute postoperative, acute delayed, and chronic infections, respectively. Of the 10 variables considered as potential risk factors, only Staphylococcal organisms predicted failure. Conclusions: Irrigation and débridement is unlikely to control periprosthetic joint infection, including acute infections. Our data suggest surgeons should be cautious using this procedure as a routine means to address periprosthetic joint infection. For most patients, we recommend irrigation and débridement be reserved for an immunologically optimized host infected acutely with a non-Staphylococcal organism. Level of Evidence: Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.