Background: Epidermolysis bullosa (EB) is frequently complicated by skin infection, which can lead to bacteremia. However, bloodstream infections (BSI) in patients with EB have not been well described. Methods: Retrospective study of BSI in children 0–18 years with EB from a national reference unit in Spain, in 2015–2020. Results: Among 126 children with EB, we identified 37 BSI episodes in 15 patients (14 recessive dystrophic EB, 1 junctional EB). The most frequent microorganisms were Pseudomonas aeruginosa (n = 12) and Staphylococcus aureus (n = 11). Five P. aeruginosa isolates were ceftazidime-resistant (42%), 4 of which were also resistant to meropenem and quinolones (33%). As for S. aureus, 4 (36%) were methicillin-resistant and 3 (27%) clindamycin-resistant. In 25 (68%) BSI episodes skin cultures had been performed in the previous 2 months. The most frequent isolates were also P. aeruginosa (n = 15) and S. aureus (n = 11). In 13 cases (52%), smear and blood cultures grew the same microorganism, with the same antimicrobial resistance pattern in 9 isolates. Twelve patients (10%) died during follow-up (9 RDEB and 3 JEB). BSI was the cause of death in 1 case. In patients with severe RDEB, a history of BSI was associated with higher mortality (OR 6.1, 95% CI: 1.33–27.83, P = 0.0197). Conclusions: BSI is an important cause of morbidity in children with severe forms of EB. The most frequent microorganisms are P. aeruginosa and S. aureus, with high rates of antimicrobial resistance. Skin cultures can help guide treatment decisions in patients with EB and sepsis.