Background: Postoperative infection is a potentially devastating complication after THA and TKA. In the early postoperative period, clinicians often find nonspecific indicators of infection. Although leukocytosis may be a sign of a developing infection in the early postoperative period, it may also be part of a normal surgical response. Questions and Purposes: We determined (1) the natural history of white blood cell values after primary THA and TKA, (2) factors associated with early postoperative leukocytosis, and (3) the predictive value of white blood cell count for early postoperative periprosthetic joint infection. Patients and Methods: Using our institutional database, we identified all THA and TKA cases between January 2000 and December 2008. We determined the incidence of leukocytosis and characterized the natural history of postoperative white blood cell counts. We then investigated potential indicators of postoperative leukocytosis, including development of early periprosthetic infection. Results: The average postoperative white blood cell count increased to approximately 3 × 10 6 cells/μL over the first 2 postoperative days and then declined to a level slightly higher than the preoperative level by Postoperative Day 4. The incidence of postoperative leukocytosis for all patients was 38%. Factors associated with postoperative leukocytosis included TKA, bilateral procedures, older age, and higher modified Charlson Comorbidity Index. The sensitivity and specificity of white blood cell count for diagnosing early periprosthetic infection were 79% and 46%, respectively. Conclusions: Postoperative leukocytosis is common after THA and TKA and represents a normal physiologic response to surgery. In the absence of abnormal clinical signs and symptoms, postoperative leukocytosis may not warrant further workup for infection. Level of Evidence: Level III, diagnostic study. See Guidelines for Authors for a complete description of levels of evidence.