Patients with α₁-antitrypsin (α₁-AT) deficiency are at risk of developing early-onset panlobular basal emphysema, which has been attributed to uncontrolled proteolytic activity within the lung. Severe genetic deficiency of α₁-AT is most commonly due to the Z mutation (342Glu→ Lys), which results in a block in α₁-AT processing within the endoplasmic reticulum of hepatocytes. The retained α₁-AT forms inclusions, which are associated with neonatal hepatitis, juvenile cirrhosis, and hepatocellular carcinoma. Our recent studies have shown that the accumulation of α₁-AT is due to the Z mutation perturbing the structure of α₁-AT to allow polymer formation, with a unique linkage between the reactive center loop of one α₁-AT molecule and the A β-pleated sheet of a second. The detection of loop-sheet polymers and other conformations of α₁-AT in the lungs of patients with emphysema has been technically difficult. We show here that transverse urea-gradient-gel (TUG) electrophoresis and Western blot analysis may be used to characterize conformations of α₁-AT in dilute samples of bronchoalveolar lavage fluid (BALF). This technique was used to demonstrate loop-sheet polymers in the lungs of patients with Z α₁-AT-deficiency-related emphysema. Polymers were the predominant conformational form of α₁-AT in BALF from the lungs of two of five Z homozygotes with emphysema, but were not detectable in any of 13 MM, MS, or MZ α₁-AT controls. Because α₁-AT loop-sheet polymers are inactive as proteinase inhibitors, this novel conformational transition will further reduce the levels of functional proteinase inhibitor in the lungs of the Z α₁-AT homozygote, and so exacerbate tissue damage.