Introduction and study aim: prolonged fever and lymphadenopathy (LAP) are two interrelating features that constitute a diagnostic challenge in medical practice. With the great variety in differential diagnoses, a wise clinical impression is needed to reach a provisional diagnosis. This is achieved through knowledge and awareness of the prevalent etiologies among our population. Patients and methods: We included 269 patients with prolonged fever and lymphadenopathy to have an excisional biopsy to reach a definitive diagnosis via histopathological examination. In addition, laboratory tests were performed to assess the role of serology to predict probable diagnoses. Results: Three main etiologies of prolonged fever and lymphadenopathy were detected; malignancy (41.7%), followed by non-specific changes (reactive hyperplasia) (30.5%), then infections (27.8%). The most commonly involved lymph nodes were cervical and axillary, then inguinal. More than half of the patients had only fever and lymphadenopathy, while cachexia and anorexia were the most common associated presentations among others. Most of the patients had high ESR level, whereas high LDH and CRP levels presented in nearly 34% and 22% of them respectively. High CRP, eosinophilia and elevated LDH, characterized malignancy whilst infection was commonly associated with lymphocytosis, monocytosis and high ESR. Old age and high ESR were significant independent predictors of malignancy, and lymphocytosis was a significant predictor of infection. Conclusion: In our region, malignancy is the commonest etiology for fever and lymphadenopathy, in addition to reactive hyperplasia and infections, respectively.