Epidemiological studies support a hypothesis that pulmonary hypertension (PH) is a common complication of sickle cell disease (SCD) that is associated with a high risk of death and evolves as a complication of haemolytic anaemia. This fundamental hypothesis has been recently challenged and remains controversial. In order to further test this hypothesis in a large and independent cohort of SCD patients we obtained plasma samples from the Cooperative Study of Sickle Cell Disease (CSSCD) for analysis of a biomarker, N‐terminal‐pro brain natriuretic peptide (NT‐proBNP), which is elevated in the setting of pulmonary arterial and venous hypertension. A NT‐pro‐BNP value previously identified to predict PH in adults with SCD was used to determine the association between the risk of mortality in 758 CSSCD participants (428 children and 330 adults). An abnormally high NT‐proBNP level ≥160 ng/l was present in 27·6% of adult SCD patients. High levels were associated with markers of haemolytic anaemia, such as low haemoglobin level (P < 0·001), high lactate dehydrogenase (P < 0·001), and high total bilirubin levels (P < 0·007). A NT‐proBNP level ≥160 ng/l was an independent predictor of mortality (RR 6·24, 95% CI 2·9–13·3, P < 0·0001). These findings provide further support for an association between haemolytic anaemia and cardiovascular complications in this patient population.