Monocyte HLA-DR antigen expression and mitogen-stimulated interferon gamma production were measured sequentially on days 1, 3, 7, 14, and 21 after admission in 20 multiply injured patients (mean Injury Severity Score, 33). Ten patients recovered uneventfully and ten developed a major infection, three of whom died. Trauma resulted in immediate and profound depression of both interferon gamma production and monocyte HLA-DR antigen expression compared with controls. Interferon gamma remained below control levels for all days on which it was measured in all patients. In uninfected patients, interferon gamma production began to recover after day 7 and interferon gamma levels on day 21 were greater than on all other days. Monocyte HLA-DR antigen expression returned to normal between days 7 and 14 in uninfected patients, despite subnormal production of interferon gamma. Failure to increase interferon gamma production and monocyte HLA-DR antigen expression was associated with an episode of major infection. We postulate that stimulation of the immune system early after injury may reverse the defects reported and decrease the incidence of infection after severe trauma.