Cystic fibrosis (CF) lung disease severity is influenced by unknown genetic factors apart from the disease causative gene, cystic fibrosis transmembrane conductance regulator (CFTR). Previous studies have shown the C57BL/6J congenic Cftr(-/-) (B6 CF) mouse to develop a fibrotic lung disease compared with both CF mice of the BALB/c background and wild-type animals. In this report, gene expression profiling with microarrays was used to identify genes differentially expressed in the lungs of B6 and BALB CF mice compared with non-CF littermates. Seven hundred two genes or expressed sequence tags (ESTs) were identified to be differentially expressed between the B6 CF and non-CF control lungs (P < 0.05), and, by Gene Ontology classification, the B6 CF response included the cell proliferation categories of DNA metabolism and mitosis. In the response of BALB mice to nonfunctional Cftr, 943 genes/ESTs were differentially expressed compared with controls. The biological processes of apoptosis and T and B cell proliferation were prominent in the gene list of the BALB CF strain. In support of this strain difference, increased T lymphocyte infiltration was evident in the lungs of BALB CF mice, through immunohistochemical staining, compared with the lungs from both B6 CF and non-CF control mice. Four hundred forty-four genes/ESTs were differentially expressed between B6 CF and BALB CF mice (P < 0.05, fold > 2), including 56 that map to previously identified linkage intervals. These results suggest that the variable severity of CF lung disease in this mouse model is controlled by multiple genetic factors, including those of an immune response.