Febrile temperatures commonly are seen after total knee arthroplasty, but their source and importance are unclear. The goal of the current study was to determine whether such fevers are part of the normal physiologic response to surgery mediated by inflammatory cytokines. In 20 patients who had total knee arthroplasty, serum and wound drain fluid samples were collected preoperatively and at 1, 6, 24, and 48 hours postoperatively; oral temperatures were measured postoperatively every 4 hours for 3 days. Concentrations of interleukin 1beta, interleukin 6, and tumor necrosis factor alpha in the samples were measured via enzyme-linked immunosorbent assays and compared in patients who did and did not have fevers develop (>or=38.5 degrees C). Gender, age, operative time, amount of blood loss or drain output, anesthesia type, drop in hematocrit, and transfusion administration were not associated with fever. Significant increases were seen postoperatively in drain fluid concentrations of interleukin 1beta and interleukin 6 and in serum concentrations of interleukin 6. Patients who were febrile had significantly higher drain and serum interleukin 6 concentrations than patients who were afebrile. These findings suggest that fevers seen after total knee arthroplasty are at least partly the result of surgical site inflammation and subsequent local and systemic release of the endogenous pyrogen interleukin 6.