LGR5 is a Wnt pathway associated G-protein-coupled receptor and a potential stem cell marker for multiple tissues. LGR5 has been found to be overexpressed in various types of human cancers and is significantly associated with poor clinical outcome. This study investigated the impact of LGR5 as well as of its splice variant LGR5Δ5 on tumor-associated parameters. Through knock-down or overexpression of LGR5FL or LGR5Δ5 in different cancer cells, the expression levels of LGR5FL/LGR5Δ5 was found to be related to clonogenicity, migration and spheroid formation as well as to expression levels of EMT markers and Wnt target genes in a cell line specific manner. Remarkably, the overexpression of the LGR5Δ5, the variant lacking the postulated ligand interaction interface, was found to induce analogous effects to overexpression of full length LGR5. Furthermore, the mRNA level of LGR5Δ5, but not of LGR5FL, was identified as an independent prognostic marker correlated with a poor outcome of STS or OSCC patients. Taken together, these results demonstrate that LGR5 is involved in vitro and in vivo in processes affecting proliferation, dissemination und EMT.