GD2 ganglioside has been identified as a key determinant of bone marrow-derived mesenchymal stem cells (BM-MSCs). Here, we characterized GD2 ganglioside expression and its implications in umbilical cord blood-derived MSCs (UCB-MSCs). Using immune-selection analysis, we showed that both GD2-positive and GD2-negative UCB-MSCs expressed general stem cell markers and possessed mesodermal lineage differentiation potential. Although the fraction of GD2-expressing cells was lower in UCB-MSC than in BM-MSC populations, inhibition of GD2 synthesis in UCB-MSCs suppressed neuronal differentiation and down-regulated basic helix-loop-helix (bHLH) transcription factors, which are involved in early stage neuronal differentiation. In addition, the levels of bHLH factors in neuronally induced UCB-MSCs were significantly higher in GD2-positive than GD2-negative cells. Our data demonstrate that GD2 ganglioside expression is associated with regulation of bHLH factors and identify neurogenic-capable UCB-MSCs, providing new insights into the potential clinical applications of MSC-based therapy.