A growing body of evidence has confirmed the involvement of dysregulated expression of HOX genes in cancer. HOX genes are a family of 39 transcription factors, divided in 4 clusters (HOXA to HOXD), that during normal development regulate cell proliferation and specific cell fate. In the present study it was investigated whether genes of the HOXB cluster play a role in oral cancer. We showed that most of the genes in the HOXB network are inactive in oral tissues, with exception of HOXB2, HOXB7 and HOXB13. Expression of HOXB7 was significantly higher in oral squamous cell carcinomas (OSCC) compared to normal oral mucosas. We further demonstrated that HOXB7 overexpression in HaCAT human epithelial cell line promoted proliferation, whereas downregulation of HOXB7 endogenous levels in human oral carcinoma cells (SCC9 cells) decreased proliferation. In OSCCs, expression of HOXB7 and Ki67, a marker of proliferation, correlate strongly with each other (rs=0.79, p<0.006). High immunohistochemical expression of HOXB7 was correlated with T stage (p=0.06), N stage (p=0.07), disease stage (p=0.09) and Ki67 expression (p=0.01), and patients with tumors showing high number of HOXB7-positive cells had shorter overall survival (p=0.08) and shorter disease-free survival after treatment (p=0.10) compared with patients with tumors exhibiting low amount of HOXB7-positive cells. Our data suggest that HOXB7 may contribute to oral carcinogenesis by increasing tumor cell proliferation, and imply that HOXB7 may be an important determinant of OSCC patient prognosis.