Although systemic lupus erythematosus (SLE) is known to be positively associated with certain major histocompatibility complex (MHC) class I and/or class II antigens, it is not clear whether the MHC genes are the predisposing genes of the disease rather than markers for other closely linked gene(s). Because of the involvement of tumor necrosis factor (TNF) in the inflammation process and localization of the TNF genes in the proximity of the HLA-B locus, we studied the restriction fragment length polymorphism (RFLP) of the TNF-alpha and -beta genes in 20 SLE patients and 23 normal individuals using restriction endonuclease NcoI. The frequency of a 5.5 kb NcoI fragment from SLE patients was significantly higher than that from normal controls. This result suggests that the polymorphic TNF genes may be involved in the pathogenesis of SLE.