A strong correlation exists between smoking and lung cancer; however, susceptibility to lung cancer among smokers is not uniform. Similarly, mice show differential susceptibility to the tobacco carcinogen nitrosamine 4- (methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) that produces lung tumors in A/J but not in C3H mice. Host immunity may play a role in susceptibility to cancer, and cigarette smoke/nicotine suppresses the immune system through activation of nicotinic acetylcholine receptors (nAChRs). Mammalian lungs express 7-nAChRs, and NNK is a high-affinity agonist for 7-nAChRs. To examine whether NNK differentially modulates the lung immunity in susceptible and resistant mouse strains, A/J and C3H mice were treated with NNK and/or immunized with sheep red blood cells (SRBC). Lung tissues and RNA of treated and untreated animals were analyzed by immunohistochemistry and RT-PCR for 7-nAChR and COX-2 expression. Spleen and the lung-associated lymph node cells from control and immunized animals were assessed for immunological responses, including anti-SRBC antibody plaque-forming cells, concanavalin A-induced T-cell proliferation, and the anti-CD3/CD28 antibody-induced rise in intracellular calcium. NNK strongly suppressed these responses in A/J but not in C3H mice. Similar NNK-induced immunological changes were also seen in another pair of carcinogen-sensitive (NGP) and relatively carcinogen-resistant (B10.A) mouse strains. Moreover, NNK stimulates a significantly higher expression of COX-2 and 7-nAChRs in A/J than in C3H lungs. These results suggest that the susceptibility to chemical carcinogenesis among various mouse strains might be influenced by their immunological response to the carcinogen.