Background: Mesenchymal stromal cells (MSC) from bone marrow have been reported to undergo the initial phases of neural differentiation in response to an increase of intracellular cAMP. We investigated the possibility that a similar effect applies to chorion-derived MSC. Methods: The intracellular concentration of cAMP was increased either by forskolin, to promote its synthesis, or by inhibitors of its degradation. The consequent reduction in the expression of mesenchymal markers was associated with the appearance of neuron-like morphology in a subset of cells. The effect was measured and characterized using biomarkers and an inhibitor of cAMP response element-binding protein (CREB). Results: The dramatic morphological change induced by all the treatments that promoted intracellular cAMP was transient and peaked on the third day. After that, cells returned to the typical fibroblast-like appearance within 24 hours. The distinctive morphology was associated to the expression of neuregulin 1, doublecortin, neuron-specific class III \beta-tubulin, and required cAMP response element-binding protein activity. Basic-fibroblast growth factor (b-FGF) treatment increased both the timeframe and number of cells undergoing the morphological change induced by the effect of forskolin. As opposite, arginine-vasopressin (AVP) and sphingosine-1-phosphate (S1P) reduced it. Conclusions: We conclude that cAMP and the ensuing CREB activation trigger a preliminary step towards neuronal differentiation of chorion-derived MSC. However, likewise other MSC, the stimulus is not sufficient to promote stable differentiation.