Disseminated Mycobacterium avium complex (MAC) infection is associated with considerable morbidity and mortality in patients with AIDS. Because both tumor necrosis factor-alpha (TNF-alpha) and 1,25-dihydroxyvitamin D3 (1,25D) may be involved in the normal control of MAC infection, these parameters were studied in AIDS patients with disseminated MAC infection. Of 53 AIDS patients studied, 24 had no clinical events, 11 had disseminated MAC infection, and 18 had other clinical events. Patients with disseminated MAC infection had significantly higher serum levels of both TNF-alpha and soluble TNF receptors compared with other AIDS patients; almost half of the MAC-infected patients had TNF bioactivity in serum. MAC-infected patients also had severely decreased serum 1,25D levels compared with all other AIDS patients. The activation of the TNF system was significantly correlated with the degree of 1,25D deficiency. These findings may reflect interaction between vitamin D and the TNF system in the pathophysiology of disseminated MAC infection in AIDS.