Despite significant improvement in the diagnosis and treatment of various human carcinomas, the 5-year survival rate for lung cancer remains below 20%. Vasoactive intestinal peptide (VIP) is an important neuropeptide in the control of lung physiology, and exerts its functions mainly through two receptor subtypes, VPAC1 and VPAC2. Receptors for VPAC1 and VPAC2 are present in human lung cancer cells, but very limited information exists about the mRNA expression of these VIP receptor subtypes in lung cancer specimens. The aim of the present study was to investigate by RT-PCR the mRNA expression of the VPAC1 and VPAC2 receptors in surgical specimens of 43 human lung cancer specimens and 7 normal lung samples. mRNA expression of the VPAC1 receptor was detected in 51% of the tumor specimens, while the incidence of mRNA expression for VPAC2 was 46%. Twenty-one percent of the tumor samples expressed only the VPAC1 receptor and 16% displayed only the VPAC2 receptor, while 13 samples (30%) expressed neither subtype. Thirteen cancer tissue specimens (30%), expressed both of these VIP receptor subtypes. Three normal lung tissue specimens also displayed gene expression for VPAC1 and/or VPAC2 receptors. Our results support the additional investigation of the role of VIP and its receptors in human lung cancer and suggest a further development of VIP analogs for therapeutic and imaging purposes in this malignancy.