Several evidences indicate that PPARgamma stimulation promotes neuronal differentiation. However, to date, no data describe the effects of PPARgamma agonists on neurite outgrowth. Here we have evaluated the effects of pioglitazone, a synthetic PPARgamma agonist, on differentiation and neurite outgrowth in SH-SY5Y human neuroblastoma cells. Our results show that pioglitazone promotes cell differentiation and the outgrowth of cell processes in a concentration-dependent manner with the maximal effect at 100 nM-1 microM. It significantly increases both the mean process length and the percentage of neurite-bearing cells. In addition, these effects are accompanied by significant activation of p42 and p44 mitogen-activated protein kinases. In conclusion, albeit preliminary, these findings suggest the possibility that PPARgamma stimulation may contribute to the development and maintenance of a proper neuronal connectivity within neuronal networks.