To determine whether tumor necrosis factor (TNF) and interleukin-1 (IL-1) might be involved in the pathogenesis of sickle cell disease and its complications, TNF-alpha and IL-1-alpha were measured using enzyme-linked immunosorbent assay in 59 plasma samples from 34 adult subjects with Hb SS or Hb SC who did not have documented infections. Tumor necrosis factor was elevated on at least one occasion in 27 subjects, including 18 of 21 subjects in the steady state and 13 of 19 subjects during painful crisis. Interleukin-1 was elevated on at least one occasion in 6 subjects, including 3 subjects in the steady state and 3 subjects in crisis. All subjects with elevated IL-1 also had elevated TNF. Tumor necrosis factor and IL-1 were similarly elevated in the steady state and during painful crisis. No correlation was noted between TNF or IL-1 levels and the extent of activation of coagulation, as measured by plasma levels of the fibrin D-dimer fragment, the overall severity of vascular occlusive disease in each subject, or the presence of specific vascular occlusive complications. We conclude that plasma TNF is frequently elevated in subjects with sickle cell disease, and IL-1 is also elevated in some subjects. A direct role for these cytokines in the pathogenesis of vascular occlusion in sickle cell disease was not demonstrated, but an indirect role was not excluded.