A multi-center study of 563 periprosthetic joint infections (PJIs) found that 16.5 % were culture negative. These patients more often had prior revision or PJI, longer symptom duration and fewer systemic signs. On multivariable analysis, symptom duration >12 weeks was the only independent risk factor (odds ratio 2.24). The findings support the fact that culture-negative infections present insidiously, informing diagnostic strategies.