Childhood community-acquired pneumonia (CAP) is a leading cause of morbidity and mortality worldwide, but studies on the treatment of children hospitalized with CAP are limited. Although ampicillin/sulbactam is frequently used to treat the pediatric population there are very limited data about the effect of the parenteral form for childhood CAP. Hence, a retrospective study was conducted to assess clinical response to empirical parenteral ampicillin/sulbactam among children hospitalized with CAP. A total of 501 children with presumed bacterial etiology and treated with intravenous ampicillin/sulbactam were included in the study. Treatment was defined as failure if the initial ampicillin/sulbactam therapy was changed because of no clinical improvement 72 h or more after its use or clinical worsening at any time. Thirty-one (6.2%) children needed treatment change whereas 470 (93.8%) were treated successfully with ampicillin/sulbactam. In multivariate analysis, male gender [OR (95%CI): 3.32 (1.37-8.04), p = 0.008], CRP levels [OR (95%CI) 1.04 (1.01-1.08), p = 0.024], and existence of pleural effusion [OR (95%CI) 5.74 (2.17-15.15), p = 0.0001] were found to be significantly associated with treatment failure for the whole study group. For the subgroup of children between 3 and 60 months of age; respiratory rate [OR (95%CI) 1.06 (1.02-1.10), p = 0.0006] was also found to be an additional risk factor. In conclusion, this is the largest study showing that empiric parenteral ampicillin/sulbactam is effective, safe, and well tolerated for treatment of children hospitalized with CAP. However, pleural effusion was found to be the main factor associated with treatment failure.