Cadherins belong to a family of homophilic cell-cell adhesion proteins that are responsible for the establishment of a precise cell architecture and tissue integrity. Moreover, experimental data suggest that loss of intercellular adhesion is inversely correlated with cellular differentiation. Furthermore, dedifferentiation is closely linked to tumor progression. Recently, we have shown that a secreted 50 kDa N-terminal fragment of P-cadherin plays a role in the progression of malignant melanoma. In this study, we have detected both the full-length and the truncated versions of P-cadherin in cell lysates of differentiated head and neck oral squamous cell carcinoma cell lines, whereas in cell lysates of dedifferentiated cell lines, we detected only the truncated 50 kDa version of P-cadherin. Treatment of the cell lines with a recombinantly expressed biotinylated, soluble 50 kDa form of the N-terminal part of P-cadherin revealed a major effect on cell aggregation and migration of oral squamous cell carcinoma cells. However, the 50 kDa N-terminal fragment of P-cadherin did not show any influence on cell proliferation in 2D and 3D cell culture. These results suggest that generation of truncated P-cadherin during the progression of oral squamous carcinoma attenuates tissue integrity, facilitates cellular separation, and leads to the acquisition of a more migratory phenotype.