Culture-negative (CN) prosthetic joint infection (PJI) has not been well studied. We performed a retrospective cohort study to define the demographic characteristics and determine the outcome of patients with CN PJI.All cases of CN total hip arthroplasty and total knee arthroplasty infections (using a strict case definition) treated at our institution from January 1990 through December 1999 were analyzed. Kaplan-Meier survival methods were used to determine the cumulative probability of success.Of 897 episodes of PJI during the study period, 60 (7%) occurred in patients for whom this was the initial episode of CN PJI. The median age of the cohort was 69 years (range, 36-87 years). Patients had received a prior course of antimicrobial therapy in 32 (53%) of 60 episodes. Of the 60 episodes, 34 (57%), 12 (20%), and 8 (13%) were treated with 2-stage exchange, debridement and retention, and permanent resection arthroplasty, respectively. The median duration of parenteral antimicrobial therapy was 28 days (range, 0-88 days). Forty-nine (82%) of 60 episodes were treated with a cephalosporin. The 5-year estimate of survival free of treatment failure was 94% (95% confidence interval, 85%-100%) for patients treated with 2-stage exchange and 71% (95% confidence interval, 44%-100%) for patients treated with debridement and retention.CN PJI occurs infrequently at our institution. Prior use of antimicrobial therapy is common among patients with CN PJI. CN PJI treated at our institution is associated with a rate of favorable outcome that is comparable to that associated with PJI due to known bacterial pathogens.