Crizanlizumab is an anti-P-selectin monoclonal antibody indicated to reduce the frequency/prevent recurrence of vaso-occlusive crises (VOCs) in patients with sickle cell disease (SCD) aged ≥16 years. This analysis of an ongoing phase 2, non randomized, open-label study reports the pharmacokinetics (PK), pharmacodynamics (PD), safety and efficacy of crizanlizumab 5.0 (N = 45) and 7.5 (N = 12) mg/kg in SCD patients with a history of VOCs (NCT03264989). Median treatment duration was 104.7 and 85.7 weeks in the 5.0 and 7.5 mg/kg groups, respectively. For both doses, serum crizanlizumab concentrations rose to near maximum levels shortly after infusion and near complete and sustained ex vivo P-selectin inhibition was observed. Grade ≥3 adverse events (AEs) occurred in 48.9% and 33.3% of patients in the 5.0 and 7.5 mg/kg groups, respectively; only one event was deemed treatment related (7.5 mg/kg group). No treatment-related serious AEs (SAEs) occurred. One infusion-related reaction was recorded (5.0 mg/kg, grade 2 'pain during infusion'), which resolved without treatment withdrawal. Infections occurred in 57.8% and 41.7% of patients in the 5.0 and 7.5 mg/kg groups, respectively; none were drug related. No treatment-related bleeding events were reported. No patients developed immunogenicity. Median (range) absolute reduction from baseline in annualized rate of VOCs leading to a healthcare visit was -0.88 (-14.7 to 13.3) and -0.93 (-2.0 to 0.4) in the 5.0 and 7.5 mg/kg groups, respectively. Results here demonstrate the PK/PD properties of crizanlizumab in SCD patients, and the potential sustained efficacy and long-term safety of the drug after >12 months' treatment. This trial is registered at www.clinicaltrials.gov as NCT03264989.