IL-6 has been shown to be a plasmacytoma growth factor in mice and is believed to play a key role in the development of human multiple myeloma. We investigated the IL-6 requirements for the growth of two human myeloma cell lines, U 266 and RPMI 8226. These cell lines secreted minute amounts of IL-6 (20 U/ml) and featured IL-6 mRNA. IL-6 receptors were detectable at the surface of malignant cells by immunofluorescence. Antibodies to IL-6 did not alter the proliferation of these myeloma cells. There was a dose-dependent decrease, however, in [3H]-thymidine uptake in the presence of IL-6 antisense (and not sense) oligodeoxynucleotides; in the presence of 20 microM IL-6 antisense, an 80 and 95% inhibition of the proliferation of U 266 and RPMI 8226 cells was observed, respectively. These results provide strong evidence for an IL-6 autocrine proliferation of myeloma cells which may occur via internal interaction between IL-6 and the IL-6 receptor.