The objective was to investigate the relation between serum levels of interferon-alpha (IFN-alpha), the activity of an endogenous IFN-alpha inducing factor (SLE-IIF), clinical and immunological disease activity as well as serum levels of antiretroviral antibodies in SLE. Serum levels of IFN-alpha were measured in serial sera from 30 patients sampled at different stages of disease activity (SLEDAI score). The SLE-IIF activity was measured by its ability to induce IFN-alpha production in cultures of normal peripheral blood mononuclear cells. Both serum IFN-alpha and SLE-IIF increased markedly at flare in serially followed patients. The SLEDAI score, levels of anti-dsDNA antibodies and IL-10 correlated positively, and complement components Clq, C3 and leukocytes correlated inversely with serum concentrations of IFN-alpha. The extent of multiple organ involvement correlated with serum IFN-alpha. No relation between concentrations of retroviral peptide binding antibodies and IFN-alpha or SLE-IIF activity was found. The close relationship between disease activity in SLE patients and IFN-alpha serum levels suggests that activation of the type 1 IFN system might be of importance in the disease process.