Recent studies suggest that activation of peroxisome proliferator-activated receptor beta/delta (PPAR|/) promotes cancer cell survival. We previously demonstrated that a selective PPAR/ agonist, GW501516, stimulated human non-small cell lung carcinoma (NSCLC) cell growth. Here, we explore the mechanisms responsible for this effect. We show that GW501516 decreased phosphate and tensin homologue deleted on chromosome 10 (PTEN), a tumor suppressor known to decrease cell growth and induce apoptosis. Activation of PPAR/ and phosphatidyl inositol 3-kinase (PI3-K)/Akt signaling was associated with inhibition of PTEN. GW501516 increased NF-B DNA binding activity and p65 protein expression through activation of PPAR/ and PI3-K/Akt signals, and enhanced the physical interactions between PPAR/ and p65 protein. Conversely, inhibition of PI3-K and silencing of p65 by small RNA interference (siRNA) blocked the effect of GW501516 on PTEN expression and on NSCLC cell proliferation. GW501516 also inhibited IKB protein expression. Silencing of IKB enhanced the effect of GW501516 on PTEN protein expression and on cell proliferation. It also augmented the GW501516-induced complex formation of PPAR/ and p65 proteins. Overexpression of PTEN suppressed NSCLC cell growth, and eliminated the effect of GW501516 on phosphorylation of Akt. Taken together, our observations suggest that GW501516 induces the proliferation of NSCLC cells by inhibiting the expression of PTEN through activation of PPAR/, which stimulates PI3-K/Akt and NF-B signaling. Overexpression of PTEN overcomes this effect and unveils PPAR/ and PTEN as potential therapeutic targets in NSCLC.