The molecular mechanisms underlying the chemopreventive effects of NSAIDs are not well understood and remain the subject of debate. One of the mechanistic possibilities involves alterations in gene expression. We examined gene expression profiles in SNU601 gastric cancer cells treated with sulindac sulfide (50 microM) for 24 hr. Microarray analysis showed that 1.3% (105/8170) of genes were induced or repressed more than 3-fold in cells treated with sulindac sulfide. Seven genes were selected and confirmed by reverse transcription-polymerase chain reaction. Inhibitor of differentiation/DNA binding-1 (Id-1) was downregulated in SNU601 cells treated with sulindac sulfide. Id-1 expression level was decreased dose-dependently by sulindac sulfide. In addition, the expression pattern of Id-1 was inversely related to that of nm23. We also examined Id-1 expression in human gastric cancer tissues and compared it with clinicopathologic parameters to study its biologic role in the cancers. Id-1 was frequently and strongly expressed in gastric cancer tissues compared with that in adjacent nonmetaplastic mucosa. Its immunoreactivity scores were positively correlated to Ki67 labeling indices and tumor progression, and is higher in intestinal type than in diffuse type. In summary, a number of genes, both induced and repressed, could be important in mediating sulindac sulfide-induced cell death in gastric cancer cells. Id-1, one of the repressed genes, is upregulated in gastric cancers and has positive role in tumor progression and histogenesis of intestinal-type cancers.