Fever is often present during painful vaso-occlusive crisis (VOC) in sickle-cell disease (SCD), but does not always indicate infection. The aim of our study was to test procalcitonin as a marker of invasive bacterial infection in VOC. Consecutive SCD adults hospitalized for VOC were included. Data were collected at admission and within 24 h after the onset of fever. We distinguished patients with clinically defined and microbiologically documented invasive bacterial infection from patients with no evidence of invasive bacterial infection and who fared well without antibiotics. One hundred and twelve patients were enrolled (61% females, median age 23 years, 88% homozygous SCD). All patients with procalcitonin (PCT) level ≥1 μg/L had an invasive bacterial infection, but two patients (33%) with an invasive bacterial infection had a PCT level <1 μg/L. High levels of PCT indicate invasive bacterial infection. However, a single low PCT level without follow-up measurement cannot rule out an invasive bacterial infection and should not withhold the prescription of antibiotics.