Orphan nuclear receptors constitute a subgroup of the superfamily of steroid/thyroid/retinoid receptors for which no endogenous ligand has been identified. The orphan nuclear receptor ROR alpha has been shown to be involved in the control of cell growth and differentiation. We have previously shown that, in DU 145 androgen-independent prostate cancer cells, ROR alpha activation brings about a significant decrease of cell proliferation and affects cell cycle progression through the modulation of cell cycle-related genes. The experiments here described have been performed to clarify whether ROR alpha might also be involved in the control of the metastatic behavior of DU 145 cells. We have shown that the thiazolidinedione derivative CGP 52608, the specific ROR alpha ligand and activator, reduces the ability of DU 145 cells to invade a reconstituted basement membrane (Matrigel). CGP 52608 also significantly decreased the capacity of prostate cancer cells to migrate towards a chemotactic stimulus (fibronectin), when plated in the upper compartment of a Boyden's chamber. Moreover, ROR alpha activation resulted in a decreased expression of alpha v beta 3 integrin and an increased level of expression of beta 4 integrin subunit. These findings indicate that the activation of the orphan nuclear receptor ROR alpha reduces the invasive and migratory capacities of androgen-independent prostate cancer cells, at least partially, by affecting integrin expression.