The present study focuses on understanding the reasons for immune dysfunction in lung cancer (LC) patients and understanding role of cyclooxygenases (COX) inhibitors in modulating anti-tumor immunity. Lymphocytes of LC patients showed decreased proliferation when stimulated with mitogens, decrease in calcium flux, low expression of activation markers and low cytotoxic response with high generation of reactive oxygen species. These lymphocytes exhibited a marked decrease in IFN- and high IL-10 with decrease in transcription factor T-bet and increased expression of GATA-3. Dissecting the signaling events demonstrated over-expression of COX-2, P-p38 MAPK and P-ERK with low expression of P-JNK1/2. Incubation of lymphocytes with specific inhibitors for ERK, p38 MAPK and COX-2 resulted in decreased IL-10 production with increase in IFN-. Under the cover of COX inhibitors significant increase in proliferation, cytotoxic response, intracellular Ca++ release and expression of activation markers was observed with decrease in reactive oxygen species. When treated with COX-2 inhibitors, the expression and activity of T-bet was increased but GATA-3 was decreased in lymphocytes. The IL-10 production in these patients, which is responsible for observed immune dysfunction is regulated by PGE2 via p38 MAPK and ERK pathways. COX-2 appears to be the focal point of prostaglandin and IL-10 production, and thus a potential target of intervention in attempts at restoring anti-tumor effector functions.