I ntegrins are a large family of transmembrane receptors that, in addition to mediating cell adhesion, modulate cell proliferation. The β_1C integrin is an alternatively spliced variant of the β₁ subfamily that contains a unique 48–amino acid sequence in its cytoplasmic domain. We have shown previously that in vitro β_1C inhibits cell proliferation and that in vivo β_1C is expressed in nonproliferative, differentiated epithelium and is selectively downregulated in prostatic adenocarcinoma. Here we show, by immunohistochemistry and immunoblotting analysis, that β_1C is coexpressed in human prostate epithelial cells with the cell-cycle inhibitor p27^kip1, the loss of which correlates with poor prognosis in prostate cancer. In the 37 specimens analyzed, β_1C and p27^kip1 are concurrently expressed in 93% of benign and 84%–91% of tumor prostate cells. Forced expression of β_1C in vitro is accompanied by an increase in p27^kip1 levels, by inhibition of cyclin A–dependent kinase activity, and by increased association of p27^kip1 with cyclin A. β_1C inhibitory effect on cell proliferation is completely prevented by p27^kip1 antisense, but not mismatch oligonucleotides. β_1C expression does not affect either cyclin A or E levels, or cyclin E–associated kinase activity, nor the mitogen-activated protein (MAP) kinase pathway. These findings show a unique mechanism of cell growth inhibition by integrins and point to β_1C as an upstream regulator of p27^kip1 expression and, therefore, a potential target for tumor suppression in prostate cancer.