Inflammation and angiogenesis are of importance in the pathophysiology of sickle cell disease (SCD). Recently, the chemokine stromal-derived factor-1 (SDF-1) has been shown to be a key mediator of angiogenesis and inflammation. In this study we determined serum SDF-1 levels in consecutive adult sickle cell patients during the clinically asymptomatic state as well as during painful crisis. Serum SDF-1 levels were significantly elevated in HbSS/HbSβ0-thalassaemia patients [n = 42; 5,177 pg/ml (2,438–7,246)] compared to HbSC/HbSβ+-thalassaemia patients [n = 16; 2,405 pg/ml (1,365–3,047)] and healthy HbAA controls [n = 45; 2,894 pg/ml (2,577–3,334)] (p = 0.001). No significant increments were observed during painful crisis (n = 40). SDF-1 levels were significantly higher in SCD patients with pulmonary hypertension (PHT) compared to patients without PHT. Elevated circulating SDF-1 levels occur in patients with SCD and may play a role in the pathophysiology of SCD-related PHT.