The incidence of fever of unknown origin was studied in 3 groups of patients undergoing aortic valve replacement. Fever of unknown origin was defined as a fever greater than 38.3 degrees C detected after the third postoperative day and which initiated a negative "fever work-up." Fifty patients underwent aortic valve replacement using cyropreserved allografts. Of the 49 patients who survived the operation, 13 (26%) developed fever of unknown origin. Only 1 (2%) of 51 patients, and 4 (8%) patients undergoing aortic valve replacement with a mechanical prosthesis and porcine xenograft, respectively, developed fever of unknown origin (p = 0.0034). Fever of unknown origin after allograft aortic valve replacement developed between the fourth and sixth postoperative days, with no other associated symptoms or signs. It lasted for 24 to 48 hours, and resolved without treatment. Univariate analysis revealed that fever of unknown origin occurred in younger patients (39.9 +/- 9.4 versus 50.8 +/- 11.8 years of age). The mean white blood cell count in fever of unknown origin and afebrile patients were similar (10.4 +/- 3.2 and 8.9 +/- 2.3, p = NS), both of which were significantly lower than the white blood cell count in patients with documented infection (15.0 +/- 5.2, p = 0.02; p < 0.001). No association could be demonstrated between the fever of unknown origin and gender, previous endocarditis, operative technique, cardiopulmonary bypass or cross-clamp times, ABO match, or perioperative blood transfusions. We conclude that a significant number of patients undergoing allograft aortic valve replacement develop noninfectious postoperative fever. The etiology remains unknown, but low-grade rejection cannot be excluded.