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Polyclonal intravenous immunoglobulins (IVIGs) can modulate the host immune response and may improve outcomes in some patients. In this prospective, noninterventional study, we assessed the time-course of γ-globulin concentrations in 21 patients with septic shock and evaluated the relationship of γ-globulin concentrations to disease severity and outcome. Six patients (28.5%) died. Sixteen patients (76%) had hypo-γ-globulinemia at admission: 12 (57%) had low IgG concentrations (<650 mg/dL), 2 had low IgA concentrations (<70 mg/dL), and 9 had low IgM concentrations (<40 mg/dL). Two patients had low concentrations of all three γ-globulins; these patients both died from refractory shock within 2 days. Patients with low IgG concentrations were indistinguishable at baseline from patients with normal IgG concentrations but had fewer vasopressor-free days (over 28 days) and more frequently developed acute lung injury/acute respiratory distress syndrome (3/9 vs. 10/12; P = 0.02). All deaths occurred in the patients with low IgG concentrations (6/12 vs. 0/9). There was a variable increase in κ and λ free light chains, a marker of γ-globulin synthesis, over time with no significant difference between low and normal IgG groups. This pilot study indicates that low concentrations of γ-globulins, especially IgG, are common in patients with community-acquired septic shock and persist over time even when sepsis resolves. Despite similar presentation, patients with hypo-IgG had greater vasopressor requirements, were more likely to develop acute lung injury/acute respiratory distress syndrome, and had higher mortality. Patients with low IgG concentrations may represent a logical target group to study the effects of Ig supplementation in septic shock.