Antibody autoreactivity against bactericidal/permeability-increasing protein (BPI) is strongly associated with infection in cystic fibrosis (CF), non-CF bronchiectasis (BE), and chronic obstructive pulmonary disease (COPD). We examined the pathogen-specific nature of this autoreactivity by examining antibodies to BPI in bacteremia patients . Antibodies to BPI and bacterial antigens were measured in sera by ELISA from five patient cohorts (= 214). Antibody avidity was investigated . Bacteremic patient sera (= 32) exhibited IgG antibody autoreactivity against BPI in 64.7% and 46.7% of patients with positive blood cultures for and, respectively . Autoantibody titers correlated with IgG responses to bacterial extracts and lipopolysaccharide (LPS). A prospective cohort of bacteremic patient sera exhibited anti-BPI IgG responses in 23/154 (14.9 %) patients with autoreactivity present at the time of positive blood cultures in patients with Gram-negative and Gram-positive bacteria, including 8/60 (13.3 %) patients with Chronic tissue infection with was associated with BPI antibody autoreactivity in 2/15 patients (13.3 %). Previously, we demonstrated that BPI autoreactivity in CF patient sera exhibits high avidity . Here, a similar pattern was seen in BE patient sera . In contrast, sera from patients with bacteremia exhibited low avidity . These data indicate that low-avidity IgG responses to BPI can arise acutely in response to bacteremia and that this association is not limited to This is to be contrasted with chronic respiratory infection with, suggesting that either the chronicity or the site of infection selects for the generation of high-avidity responses, with biologic consequences for airway immunity.