Prostacyclin (PGI2) plays a role in cancer progression but the mechanism is currently poorly understood. Additionally, no data are available about the prognostic value of the PGI2-pathway in head and neck squamous cell carcinoma (HNSCC) therapy. We evaluated the expression of the PGI2-pathway in HNSCC patients. PGI2 production and PGI-Synthase (PGIS) expression, in terms of mRNA (RT-PCR) and protein (immunoblotting), were lower in tumor samples than in non-tumoral mucosa, whereas, as expected, COX-2 expression was increased in HNSCC tumor samples. Using local control of the tumor after radiotherapy or chemoradiotherapy as a dependent variable, patients were classified in two categories of PGIS transcript-levels. The high-PGIS group had a significantly lower frequency of local and distant failure than the low-PGIS group, and the 5-year cancer-specific survival was higher [90.2% (CI 95%: 81.0-99.4%) vs 60.5% (CI 95%:44.4-76.6%)]. None of the four HNSCC cell lines analyzed expressed PGIS and therefore they did not produce PGI2. However, HNSCC conditioned media enhanced PGI2 production in endothelial cells (EC). The stable analog of PGI2, carbaprostacyclin (cPGI2), exerted little effect on HNSCC cell lines migration, and no effect on cell cycle distribution or proliferation rate after radiation injury was observed. Nevertheless, cPGI2 promoted EP-4-dependent in vitro angiogenesis. Von Willebrand factor expression (EC-marker) and capillary density were significantly higher in the group of patients with high-expression of PGIS. Our results indicate that PGIS expression was associated to radiotherapy efficiency. Although we do not provide direct evidence of a relationship between tumor vascularization and radiotherapy efficiency, our results suggest that the effect of PGI2 is related with its ability to promote vascularization. These results also support the concept that coadjuvant therapy with PGIS enhancers, such as retinoids, could have therapeutic value for HNSCC treatment.