During acute upper respiratory tract infections (AURTIs) caused by Adenoviruses, the mix of severe clinical presentation, together with elevation of white blood cells (WBCs) and C-reactive protein (CRP), often mimicking bacterial infection, leads to an inappropriate use of antibiotics. We studied 23 immunocompetent children admitted to our Pediatric Emergency Unit with signs of acute Adenoviral AURTIs, aiming at better clarifying the biological background sustaining this clinical presentation. Infection etiology was tested with nasopharyngeal swabs, serology, and DNA-PCR. During fever peaks and subsequent recovery, we assessed WBC count with differential, CRP, procalcitonin, serum concentration of six inflammatory cytokines, and lymphocyte subset populations. Results: IL-6 and IL-8 were found elevated in the acute phase, whereas a significant decrease during recovery was found for IL-6 and IL-10. We highlighted an increase of B lymphocytes in the acute phase; conversely, during recovery, an increase in T regulatory cells was noted. Monocytes and leukocytes were found markedly elevated during fever peaks compared to convalescence. All patients recovered uneventfully. The composition of lymphocyte population subsets and serum alterations are the main drivers of an overprescribed antibiotic. Examination of hospital admissions and performance is needed in further investigations to rule out bacterial infections or inflammatory syndromes.