The diagnosis of prolonged fevers has posed a clinical challenge for centuries. In 1907, the related concepts of “fever of unknown origin,” “fever of undetermined origin,” and “unexplained fever” appeared. The original diagnostic criteria for fever of unknown origin (FUO), established by Petersdorf and Beeson in 1961, required a fever ≥38.3 °C (101 °F) persisting for over 3 weeks, remaining undiagnosed after one week of inpatient evaluation. Evaluation of fever of unknown origin (FUO) can be conducted in the outpatient setting. Petersdorf further categorized FUO into four major groups: infectious, malignant (neoplastic), rheumatic or non-infectious inflammatory, and miscellaneous disorders. In 1991, D. T. Durack and A. C. Street refined the FUO definition initially outlined by R. B. Petersdorf in 1961. They suggested differentiating classical FUO from three specific subtypes: nosocomial FUO, neutropenic FUO, and HIV-associated FUO (Table 1.1). This refined classification reflects significant differences in disease patterns, with the latter groups more frequently associated with infections, malignancies, and drug-induced cases. Additionally, the diagnostic and management approaches for these subtypes require distinct clinical considerations. In this book, we will focus on the classical FUO.