Objective To determine the value of serum concentrations of interleukin-6 (IL-6), C-reactive protein, and glycosylation of α-acid glycoprotein as tools for diagnosing nosocomial infection in surgical intensive care unit (ICU) patients. Design Prospective, consecutive entry study of patients with an anticipated stay of at least 24 hrs in a surgical ICU. Setting University hospital, a major provider of acute surgical care. Patients One hundred four consecutive patients admitted to the surgical ICU between March and June 1990. Measurements Concentrations of IL-6, C-reactive protein, and glycosylation of α1-acid glycoprotein were measured on days 1 and 6 after ICU admission. Clinical evaluation for infection was performed daily in a blinded fashion, i.e., without knowing the results of the acute-phase parameters. Main Results On day 6 after surgery or trauma, nosocomial infection could be ascertained in 13 cases. The clinical parameter-of fever >38°C had a sensitivity of 54% and a specificity of 90% to demonstrate nosocomial infection. Infected patients showed increased concentrations of IL-6 (p < .001), C-reactive protein (p < .001), and increased reactivity of α1-acid glycoprotein to concanavalin A (p < .001) compared with patients without infections. By choosing appropriate cutoff values, IL-6 determinations had the highest specificity (97%), and C-reactive protein values had the highest sensitivity (85%) for diagnosing nosocomial infections. In uninfected patients, 81% of the IL-6 values, but only 29% of the C-reactive protein values, were back to the normal range on day 6 after injury. Conclusion Due to the rapid normalization after trauma, a single measurement of the serum IL-6 concentration may be useful to support or refute the clinical suspicion of nosocomial infection. (Crit Care Med 1993; 21:1175–1180)