The single-nucleotide polymorphism (SNP) g.1548G > A (E469K) in the human intercellular adhesion molecule-1 (ICAM-1) gene has been suggested to have an association with several types of inflammatory diseases. The polymorphism is located at the three-base position upstream of the splice donor site that produces an alternatively spliced short isoform (ICAM-1-S). To clarify its functional relevance, we studied RNA splicing patterns by comparing cells with different genotype (G/G cells and A/A cells). G/G cells expressed a lower amount of ICAM-1-S mRNA than A/A cells. Since ICAM-1-S has no transmembrane or intracellular domain, ICAM-1 signal transduction and cell-cell contact including Fas-FasL interaction may be influenced. In addition, we studied the effect of this change on FLIP-L mRNA and apoptosis. FLIP-L mRNA tended to decrease, while cell death induced by phorbol 12-myristate 13-acetate was increased. These results suggest that the g.1548 polymorphism modifies inflammatory immune responses by changing cell-cell interaction and then regulating apoptosis.