Immunocompromised patients with periprosthetic joint infection (PJI) are rare and currently there are no reliable guidelines according to which these infections can be successfully managed. The purpose of this study was to report the clinical course of different strategies for treatment of PJI in frail patients. A retrospective analysis between 2004 and 2015 included 29 immunocompromised patients (13 hips and 16 knees) with chronic PJI who underwent one-stage revision or debridement, antibiotics and implant retention (DAIR). Patients were stratified according to the Musculoskeletal Infection Society (MSIS) staging system and the clinical course included recurrence of infection and functional outcomes which were extracted from patients' charts. The average follow-up was 68 months (range, 26-149 months). Sixteen of the 29 patients had recurrent infections. At last follow-up, 13 patients were on chronic suppressive antibiotic therapy, three patients died but not one death was considered to be related to the infection. A recurrent infection was observed in 13 of the 24 medically compromised hosts (MSIS type B). Sixteen of the 24 patients underwent one-stage revision; another eight of them underwent DAIR. The infection recurred in three of the five patients (60%) with the worst host grades (MSIS type C). One-stage revision was performed in one of the five patients and the remaining four patients received DAIR. Our results show that we should compromise our expectation and intemperate treatment for such a population. The goals of PJI treatment in these patients should take into account their preferences and may pay more attention to the concept of disease control rather than cure, especially for patients with severe comorbidities (MSIS C). Therapeutic Level IV.