Stroke is a major cause of morbidity and mortality in sickle cell (SS) disease. Genetic risk factors have been postulated to contribute to this clinical outcome. The human genome project has substantially increased the catalog of variations in genes, many of which could modify the risk for manifestations of disease outcome in a monogenic disease, namely SS. VCAM1 is a cell adhesion molecule postulated to play a critical role in the pathogenesis of SS disease. We identified a total of 33 single nucleotide polymorphisms (SNPs) by sequencing the entire coding region, 2134 bp upstream of the 5' end of the published cDNA, 217 bp downstream of the 3' end of the cDNA, and selected intronic regions of the VCAM1 locus. Allelic frequencies for selected SNPs were determined in a healthy population. We subsequently analyzed 4 nonsynonymous coding, 2 synonymous coding, and 4 common promoter SNPs in a genetic association study of clinically apparent stroke in SS disease conducted in a cohort derived from a single institution in Jamaica (51 symptomatic cases and 51 matched controls). Of the 10 candidate SNPs analyzed in this pilot study, the variant allele of the nonsynonymous SNP, VCAM1 G1238C, may be associated with protection from stroke (odds ratio [OR] 0.35, 95% confidence interval [CI] 0.15-0.83, P =.04). Further study is required to confirm the importance of this variant in VCAM1 as a clinically useful modifier of outcome in SS disease.