In order to analyze the presence and the function of the "insulin-like growth factor I (IGF-I) system" in human non-small-cell lung cancer (N-SCLC) we tested 5 cell lines of different histological sub-types: A549, Ca-Lu-6, SK-Lu-1 (adenocarcinoma); Ca-Lu-1, SK-Mes-1 (squamous carcinoma) and one normal fibroblast-like fetal lung cell line (IMR-90) for expression of the IGF-I peptide and its RNA transcribed from the IGF-I gene; IGF-binding proteins (IGF-BP); IGF-I receptor (IGF-I-R) and its mRNA. In addition, we examined the capacity of exogenous human recombinant IGF-I to enhance the in vitro cell proliferation. In medium conditioned from cell cultures, we detected immunoreactive IGF-I material by radioimmunoassay. Western ligand blot and affinity labelling demonstrated the presence of several molecular species of IGF-BPs (IGF-BP-4, -1, -2, -3) as well. Northern blot analysis of polyA+ RNA from all cell lines examined revealed the presence of IGF-I and IGF-I-R mRNA. Moreover, binding studies on cultured cell lines showed one class of high-affinity, operative type-I IGF cell-surface binding sites. Finally, by thymidine uptake and colorimetric metabolic MTT assays, we found that most neoplastic cell lines react mitogenically to IGF-I and that its physiological effect is abolished by an anti-IGF-I-receptor antibody. These data indicate the importance of the IGF-I system in N-SCLC growth. Furthermore, they suggest that this mitogenic complex should be appraised as a possible target for anti-neoplastic drugs, antibodies or growth-factor analogues offering potential new approaches to therapy.