Background: Fever of unknown origin (FUO) was initially defined in 1961 as a condition where the body temperature exceeds 38.3°C on multiple occasions, lasts for over 3 weeks, or remains undiagnosed after one week of inpatient evaluation. Recently, the criteria have been updated to include patients whose condition remains undiagnosed after either three outpatient visits or three days of hospitalization. Objective: This study aimed to explore the causes, epidemiological features, and relative incidence of various FUO etiologies in the central Delta Region of Egypt. Patients and methods: This retrospective cohort study included all FUO cases documented in the file system over a four-year period (2015–2018) at Mahala-Kubra Fever Hospital Results: In this study, a total of 291 FUO cases were included. The predominant cause of FUO was infection, which was found in 254 cases (87.3%), followed by neoplasms in 19 cases (6.5%). Autoimmune and other miscellaneous causes accounted for 7 cases (2.4%), and the remaining 4 cases (1.4%) were undiagnosed. The most common infectious causes were urinary tract infections (103 cases, 40.5%) and brucellosis (93 cases, 36.6%). Other common infectious causes included typhoid fever (23cases, 9.1%), pneumonia (12 cases, 4.7%), and abscesses (3 cases, 1.2%). Among the malignant causes, hematological cancers were most common, with lymphoma being the most frequent (7 cases, 36.8%), followed by leukemia (5 cases, 26.2%). Conclusion: Fever of unknown origin (FUO) can result from a wide range of causes. In this study, the most common causes of FUO were infections, particularly urinary tract infections (UTIs) and brucellosis. Hematological cancers were also observed in a significant proportion of the cases.