Pulmonary hypertension (PH) in sickle cell disease (SCD) is an emerging and important clinical problem. In a single‐institution adult cohort of 365 patients, we investigated lipid and lipoprotein levels and their relationship to markers of intravascular haemolysis, vascular dysfunction and PH. In agreement with prior studies, we confirm significantly decreased plasma levels of total cholesterol, high‐density lipoprotein‐cholesterol (HDL‐C) and low‐density lipoprotein‐cholesterol (LDL‐C) in SCD versus ethnically‐matched healthy controls. Several cholesterol parameters correlated significantly with markers of anaemia, but not endothelial activation or PH. More importantly, serum triglyceride levels were significantly elevated in SCD compared to controls. Elevated triglyceride levels correlated significantly with markers of haemolysis (lactate dehydrogenase and arginase; both P < 0·0005), endothelial activation (soluble E‐selectin, P < 0·0001; soluble P‐selectin, P = 0·02; soluble vascular cell adhesion molecule‐1, P = 0·01), inflammation (leucocyte count, P = 0·0004; erythrocyte sedimentation rate, P = 0·02) and PH (amino‐terminal brain natriuretic peptide, P = 0·002; prevalence of elevated tricuspid regurgitant velocity (TRV), P < 0·001). In a multivariate analysis, triglyceride levels correlated independently with elevated TRV (P = 0·002). Finally, forearm blood flow studies in adult patients with SCD demonstrated a significant association between increased triglyceride/HDL‐C ratio and endothelial dysfunction (P < 0·05). These results characterize elevated plasma triglyceride levels as a potential risk factor for PH in SCD.