Interleukin-6 (IL-6) is involved in regulation of the immune response, acute phase reaction, and cell proliferation. The aim of this study was to investigate whether IL-6 is implicated in cell proliferation of human non-small-cell lung cancer (NSCLC) cell lines. We analyzed IL-6 messenger RNA (mRNA) and protein expression in eight NSCLC cell lines: A549, Calu3, Calu6, H23, H522, H810, H1155, and H1299. The A549, Calu3, Calu6, and H23 cell lines expressed IL-6 mRNA and protein. In these cell lines, fetal calf serum (FCS) significantly increased cell proliferation as assessed by thymidine incorporation. In the presence of IL-6 antisense oligonucleotides, both proliferation and IL-6 synthesis were downregulated. In contrast, IL-6 mRNA and protein could not be detected in the NSCLC cell lines H522, H810, H1155, and H1299. In these NSCLC cell lines, FCS only marginally increased cell proliferation and IL-6 antisense oligonucleotides did not affect cell proliferation. The addition of neither exogenous IL-6 nor neutralizing anti-IL-6 antibodies affected cell proliferation in any of the experiments. Our data thus provide evidence that intracellular IL-6 is required in the control of cell proliferation in a subset of human NSCLC cell lines. We suggest the existence of two subtypes of NSCLC, an IL-6-dependent and an IL-6-independent type.