Introduction. Sickle cell disease (SCD) children have a high susceptibility to pneumococcal infection. For this reason, they are routinely immunized with pneumococcal vaccines and use antibiotic prophylaxis (AP).Hypothesis/Gap Statement. Yet, little is known about SCD children's gut microbiota. If antibiotic-resistant Enterobacterales may colonize people on AP, we hypothesized that SCD children on AP are colonized by resistant enterobacteria species.Objective. To evaluate the effect of continuous AP on Enterobacterales gut colonization from children with SCD.Methodology. We analysed 30 faecal swabs from SCD children on AP and 21 swabs from children without the same condition. Enterobacterales was isolated on MacConkey agar plates and identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) (bioMérieux, Marcy l'Etoile, France). We performed the antibiogram by Vitek 2 system (bioMérieux, Marcy l'Etoile, France), and the resistance genes were identified by multiplex PCR.Results. We found four different species with resistance to one or more different antibiotic types in the AP-SCD children's group: Escherichia coli, Klebsiella pneumoniae, Citrobacter freundii, and Citrobacter farmeri. Colonization by resistant E. coli was associated with AP (prevalence ratio 2.69, 95 % confidence interval [CI], 1.98-3.67, P<0.001). Strains producing extended-spectrum ß-lactamases (ESBL) were identified only in SCD children, E. coli, 4/30 (13 %), and K. pneumoniae, 2/30 (7 %). The ESBL-producing Enterobacterales were associated with penicillin G benzathine use (95 % CI, 22.91-86.71, P<0.001). CTX-M-1 was the most prevalent among ESBL-producers (3/6, 50 %), followed by CTX-M-9 (2/6, 33 %), and CTX-M-2 (1/6, 17 %).Conclusion. Resistant enterobacteria colonize SCD children on AP, and this therapy raises the chance of ESBL-producing Enterobacterales colonization. Future studies should focus on prophylactic vaccines as exclusive therapy against pneumococcal infections.