Phospholipase Cepsilon (PLCepsilon) is a newly described effector of the small GTP-binding protein H-Ras. Utilizing H-Ras effector mutants, we show that mutants H-Ras(G12V/E37G) and H-Ras(G12V/D38N) suppressed integrin activation in an ERK-independent manner. H-Ras(G12V/D38N) specifically activated the PLCepsilon effector pathway and suppressed integrin activation. Inhibition of PLCepsilon activation with a kinase-dead PLCepsilon mutant prevented H-Ras(G12V/D38N) from suppressing integrin activation, and low level expression of H-Ras(G12V/D38N) could synergize with wild-type PLCepsilon to suppress integrins. In addition, knockdown of endogenous PLCepsilon with small interfering RNA blocked H-Ras(G12V/D38N)-mediated integrin suppression. Suppressing integrin function with the H-Ras(G12V/D38N) mutant reduced cell adhesion to von Willebrand factor and fibronectin; this reduction in cell adhesion was blocked by coexpression of the kinase-dead PLCepsilon mutant. These results show that H-Ras suppresses integrin affinity via independent Raf and PLCepsilon signaling pathways and demonstrate a new physiological function for PLCepsilon in the regulation of integrin activation.