Periprosthetic joint infection (PJI) is a devastating complication after total joint arthroplasty. Lack of confirmation of an infecting organism poses a challenge with regard to the selection of an appropriate antibiotic agent and surgical treatment. It is unclear whether patients with negative cultures presumed to have infections achieve similar rates of infection-free survival as those with positive cultures. The purposes of this study were (1) to report the infection control rates using irrigation and débridement and two-stage exchange for treatment of culture-negative PJIs; and (2) to compare infection control rates in culture-negative cases with those in culture-positive cases. We retrospectively reviewed 55 patients with culture-negative PJI treated between 2000 and 2007. We compared the infection-free survival rate in the culture-negative patients with that of 295 culture-positive cases of PJI. Overall infection control rate in culture-negative cases was 73% at minimum 1-year followup (mean, 47 months; range, 12-119 months). We found similar infection control rates in culture-negative and culture-positive PJI. Infection-free survival rates in both groups were highest after two-stage exchange arthroplasty and postoperative vancomycin therapy. Our observations suggest aggressive two-stage exchange arthroplasty and postoperative parenteral vancomycin therapy in patients with culture-negative PJI achieves similar rates of infection-free survival as with patients having culture-positive PJI. Level III, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.