Since its first rigid definition in 1961 by Petersdorf and Beeson, fever of unknown origin (FUO) has been a major clinical challenge. In this clinical investigation, a retrospective study was conducted on 153 patients meeting the classic criteria of FUO. Collagen-vascular disease was found to be the most common cause of FUO, a change since our last study conducted from 1971 to 1982, replacing infection as the most common disease category of FUO. FUO in elderly patients was also analyzed. By comparing previously documented studies, we observed a new variation in the diseases that are possible causes of FUO. This report will define the present status of FUO in Japan, as well as a comparison with our previous study and other documented studies to determine the shift in the spectrum of diseases causing FUO.