Abstract Background Lymphadenopathy (LN) affects as many as 90% of young children. A common cause of cervical LN is viral agents. The second most common cause is bacterial infections. While cancer is the most feared cause of generalized LN [2]. Objectives To define the etiology of localized versus generalized LN in children and adolescents in two tertiary centers (Ain Shams and Sultan Qaboos University Hospitals).Define the alarming signs for possible malignancy. Methods All children 2–16 years of both sexes presented to the two centers during the period 2018–2022, we divided them into patients with single lymph node enlargement and those with multiple LNs. Also with viral infection,either EBV or cytomegalovirus (CMV), and those with oncological diagnosis such as lymphoma and leukemia. Results Six hundred twenty-four children, 62% males aged 2–16 years (median, 6.5 years) over a period of 4 years,and acute both bacterial and granulomatous-related LNs were excluded (n=236). Meanwhile, 388 were enrolled from two centers, Ain Shams Children’s hospital (90%) and Sultan Qaboos (10%). In Ain Shams, 40% were referred to the general pediatrics clinic (n=155), only 1.9% were malignant, while of those referred to the pediatric oncology clinic(n=233), 42 (mostly 18%) were malignant, either leukemia (n=21) or lymphoma (four Hodgkin and seven NHL), and 10 were IMLN. Viral infection was the commonest; two-thirds were EBV and one third were CMV infection. Affected children with leukemia or NHL were commonly younger than 5 years.Boys were affected more with either EB or CMV often (two-thirds). No difference in the frequency of high temperature and sore throat between examined children in both viruses, but stomachaches, eyelid swelling, and skin rash were more common in CMV, while the frequency of LN and hepatosplenomegaly was not different. Alarming signs for risk for leukemia were associated with fever for more than 2 weeks. Purpura, bone aches and LNs. Generalized, nonregressive, firm and nontender, and splenomegaly were more at risk for noninfectious. Delay in diagnosis was 9–56 days comparable in both localized and generalized LN(mean, 17±3.1 days). Conclusion EBV was the commonest viral cause of LN in young children. Alarming signs for more serious illness were bone aches, splenomegaly, and purpura.