Community-acquired pneumonia (CAP) is the main cause of death in children under-5 years worldwide and Streptococcus pneumoniae is the most common bacterial agent. However, it is difficult to identify pneumococcal infection among children with CAP. We aimed to assess association between any cytokine/chemokine and pneumococcal infection in childhood CAP. Furthermore, we evaluated the diagnostic value of cytokine/chemokine for pneumococcal infection. This prospective study was conducted at an Emergency Room, in Salvador, Brazil. Children <5-years-old hospitalized with CAP in a 21-month period were evaluated. On admission, clinical and radiological data were collected along with biological samples to investigate 20 etiological agents and determine serum cytokines (interleukin (IL)-8, IL-6, IL-10, IL-1β, IL-12, TNF-α, IL-2, IL-4, IL-5, γ-interferon), and chemokines (CCL2, CCL5, CXCL9, CXCL10) concentration. From 166 patients with etiology detected, pneumococcal infection was detected in 38 (22.9%) cases among which the median IL-6(pg/ml) was 31.2 (IQR: 12.4-54.1). The other 128 cases had other causative agents detected (Haemophilus influenzae, Moraxella catarrhalis, atypical bacteria and viruses) with the median IL-6 concentration being 9.0 (IQR: 4.1-22.0; p < 0.001). The area under the ROC curve for IL-6 to predict pneumococcal CAP was 0.74 (95%CI: 0.65-0.83; p < 0.001). By multivariate analysis, with pneumococcal CAP as dependent variable, IL-6 was an independent predictor for pneumococcal infection (OR = 5.56; 95%CI: 2.42-12.75, cut-off point = 12.5 pg/ml; p = 0.0001). The negative predictive value of IL-6 under 12.5 pg/ml for pneumococcal infection was 90% (95%CI: 82-95%). Independently significant difference was not found for any other cytokines/chemokines. Serum IL-6 concentration on admission is independently associated with pneumococcal infection among children under-5 years hospitalized with CAP.