Clinical variability in sickle cell disease (SCD) suggests a role for extra-erythrocytic factors in the pathogenesis of vasoocclusion. We hypothesized that endothelial cell dysfunction, one possible modifier of disease variability, results from induction of phenotypic changes by circulating factors. Accordingly, we analyzed gene expression in cultured human pulmonary artery endothelial cells (HPAEC) exposed to plasma from: a) sickle acute chest syndrome (ACS) patients; b) SCD patients at steady-state, c) normal volunteers and d) serum-free media, using whole genome microarrays (U133A-B GeneChip Affymetrix). Data were analyzed by Bayesian Analysis of Differential Gene Expression (BADGE). Differential expression was defined by the probability of >1.5 fold change in signal intensity greater than .999 and a predicted score of 70-100, measured by cross validation. Compared to normal plasma, plasma from SCD patients (steady-state) resulted in differential expression of 50 genes in HPAEC. Of these genes, molecules involved in cholesterol biosynthesis and lipid transport, the cellular stress response and extracellular matrix proteins were most prominent. Another 58 genes were differentially expressed in HPAEC exposed to plasma from ACS patients. The pattern of altered gene expression suggests that plasma from SCD patients induce an EC phenotype which is anti-apoptotic and favors cholesterol biosynthesis. An altered EC phenotype elicited by SCD plasma may contribute to the pathogenesis of sickle vasoocclusion.