Peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) is a nuclear receptor involved in regulation of lipid and glucose metabolism, wound healing and inflammation. PPARbeta/delta has been associated also with cancer. Here we investigated the expression of PPARbeta/delta and components of the prostaglandin biosynthetic pathway in non-small cell lung cancer (NSCLC). We found increased expression of PPARbeta/delta, Cox-2, cPLA(2), PGES and VEGF in human NSCLC compared to normal lung. In NSCLC cell lines PPARbeta/delta activation increased proliferation and survival, while PPARbeta/delta knock-down reduced viability and increased apoptosis. PPARbeta/delta agonists induced Cox-2 and VEGF transcription, suggesting the existence of feed-forward loops promoting cell survival, inflammation and angiogenesis. These effects were seen only in high PPARbeta/delta expressing cells, while low expressing cells were less or not affected. The effects were also abolished by PPARbeta/delta knock-down or incubation with a PPARbeta/delta antagonist. Induction of VEGF was due to both binding of PPARbeta/delta to the VEGF promoter and PI3K activation through a non-genomic mechanism. We found that PPARbeta/delta interacted with the PI3K regulatory subunit p85alpha leading to PI3K activation and Akt phosphorylation. Collectively, these data indicate that PPARbeta/delta might be a central element in lung carcinogenesis controlling multiple pathways and representing a potential target for NSCLC treatment.