Primary failure of host defense mechanisms has been associated with increased infection and mortality. Anergy, the failure of delayed hypersensitivity response, has been shown to identify surgical patients at increased risk for sepsis and related mortality. The anergic and relatively anergic patients whose skin tests failed to improve had a mortality rate of 74.4%, whereas those who improved their responses had a mortality rate of 5.1% (P < 0.001). This study documents abnormalities of neutrophil chemotaxis, T-lymphocyte rosetting in anergic patients and the effect of autologous serum. These abnormalities may account for the increased infection and mortality rates in anergic patients. Skin testing with five standard antigens has identified 110 anergic (A) or relatively anergic (RA) patients in whom neutrophil chemotaxis (CTX) and bactericidal function (NBF), T-lymphocyte rosettes, mixed lymphocyte culture (MLC), cell-mediated lympholysis (CML), and blastogenic factor (BF) were studied. The MLC, CML and BF were normal in the patients studied, and were not clinically helpful. Neutrophil CTX in 19 controls was 117.5 +/- 1.6 u whereas in 40 A patients, neutrophils migrated 81.7 +/- 2.3 u and in 15 RA patients 97.2 +/- 3.8 u (P < 0.01). In 14 patients whose skin tests converted to normal, neutrophil migration improved from 78.2 +/- 5.4 u to 107.2 +/- 4.0 u (P < 0.01). Incubation of A or control neutrophils in A serum reduced migration in A patients from 93 +/- 3.7 u to 86.2 +/- 3.5 u (P < 0.01) and in normals from 121.2 +/- 1.6 u to 103.6 +/- 2.6 u (P < 0.001). The per cent rosette forming cells in 66 A patients was 42.5 +/- 3.1 compared to 53.6 +/- 2.8 in normal responders (P < 0.02). Incubation of normal lymphocytes in anergic serum further reduced rosetting by 30%. Restoration of delayed hypersensitivity responses and concurrent improvement in cellular and serum components of host defense were correlated with maintenance of adequate nutrition and aggressive surgical drainage.