The binding of 125I-VIP to human lung cancer cell lines was investigated. Radiolabeled VIP bound to adenocarcinoma, squamous cell carcinoma, large cell carcinoma and small cell lung cancer (SCLC) cell lines. As SCLC cell line NCI-N592 bound radiolabeled VIP well, its binding was further characterized. 125I-VIP bound to membranes in a specific and time dependent manner. 125I-VIP bound with high (Kd = 0.8 nM) and moderate affinity (Kd = 66 nM) to two classes of sites. Pharmacology studies indicated that the order of peptide potency was VIP much greater than PHI greater than secretin greater than VIP10-28. Because VIP receptors are present on human lung cancer cells, VIP may function as a regulatory peptide in lung cancer.