Introduction Etiological diagnosis of fever in sickle cell disease (SCD) children is often challenging. Objective: to analyze the pattern of inflammatory biomarkers in SCD febrile children and controls, in order to determine predictors of severe bacterial infection (SBI). Methods Prospective, case-control study of febrile and steady-state SCD children carried out during 3 years. Clinical characteristics and laboratory parameters, including 10 serum proinflammatory cytokines (IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-17a, IFN-γ and TNF-α) and comparisons among study subgroups were analyzed. Results A total of 137 patients (78 cases and 59 controls) were included in the study; 78.5% males, median age 4.1 (1.7-7.5) years. Four cases were diagnosed with SBI, 41 viral infection (VI) and 33 no proven infection (NPI). IL-6 was significantly higher in patients with SBI than in patients with VI or NPI (163 vs 0.7 vs 0.7 pg/ml, p < 0.001), and undetectable in all controls. The rest of the cytokines analyzed did not show any significant difference. The optimal cut-off value of IL-6 for the diagnosis of SBI was 125 pg/mL, with high PPV and NPV (PPV of 100% for a prevalence of 5, 10 and 15% and NPV of 98.7%, 97.3% and 95.8% for those prevalences, respectively). Conclusion We found that IL-6 (optimal cut-off value of 125 pg/ml) was a very good marker for SBI in this cohort of febrile SCD children, with high PPV and NPV. Therefore, IL-6 may be useful, alone or combined with other biomarkers, to guide the management of these patients.