Although HLA class I expression is diminished in patients with defects in the transporter associated with antigen presentation (TAP), recurrent Gram-negative bacterial lung infections are found from childhood onwards. As MHC class II-mediated responses are normal, other mechanisms that contribute to susceptibility to infections are presumed. The bactericidal/permeability-increasing protein (BPI) is a potent neutrophil antibiotic that neutralizes endotoxin efficiently. As antineutrophil cytoplasmic autoantibodies (ANCA) against BPI were found in the majority of cystic fibrosis patients and correlate with disease severity we examined the prevalence of BPI-ANCA and their contribution to susceptibility to bacterial infections in six TAP-deficient patients. Although only two patients showed ANCA in indirect immunofluorescence, BPI-ANCA occurred in five of six patients in ELISA. Purified IgG from BPI-ANCA-positive sera (five of six) inhibited the antimicrobial function of BPI in vitro. Epitope mapping revealed binding sites not only on the C-terminal but also on the antibiotic N-terminal portion of BPI, indicating that short linear BPI peptide fragments may be long-lived enough to become immunogens. In conclusion, BPI-ANCA are associated strongly with TAP deficiency. Inhibition of the antimicrobial BPI function by BPI-ANCA demonstrates a possible mechanism of how autoantibodies may contribute to increased susceptibility for pulmonary Gram-negative bacterial infections by diminished bacterial clearance.