Clinical and biochemical signs of lung and liver disease have been followed prospectively in a birth cohort of individuals with alpha1-antitrypsin (AAT) deficiency. At age 26 years, the focus was on clinical health, lung and liver function tests, and plasma markers of the protease/antiprotease balance. The effect of early childhood environment and symptoms was also studied. Eligible individuals were 26-year-old subjects with AAT deficiency (PiZ, n = 122; PiZ -, n = 2; PiSZ/S-, n = 53) and control subjects (PiMM, n = 44). Of the original AAT-deficient subjects, 119 completed the clinical examination and 134 answered the questionnaire. The prevalence of respiratory symptoms did not differ between the PiZ and SZ groups. Sixteen percent of PiZ and 14% of PiSZ subjects had asthma. Four current smokers (67%) and 22% of ex-smokers/never-smokers reported recurrent wheezing (p = 0.03). No difference in FEV1 or FEV1/FVC ratio was found between the PiZ, SZ (5% being smokers), and MM individuals (all nonsmokers). A decreased FEV1/FVC ratio was found in PiZ subjects with neonatal cholestasis, compared to remaining PiZ subjects (p = 0.02). Recurrent wheezers at age 2 years with AAT deficiency had decreased FEV1/FVC ratio (p = 0.025) at age 26 years. None had clinical symptoms of liver disease. Six percent of PiZ and 9% of PiSZ subjects had a marginal increase of serum alanine aminotransferase; 7% of PiZ and 4% of PiSZ had abnormal gamma-glutamyl transferase test results. The PiZ and SZ individuals had decreased plasma albumin (p = 0.0002). Secretory leukocyte protease inhibitor (SLPI) was increased in PiZ and SZ subjects compared to PiMM subjects (p = 0.0001). Neutrophil lipocalin was decreased in PiZ subjects (p = 0.0004) and PiSZ subjects (p = 0.001) compared to PiMM individuals. The elastase/AAT complex concentration was lower in AAT-deficient subjects (p = 0.0001). Twenty-six-year-old PiZ and SZ individuals (5% smokers) had normal lung function test results, and 4 to 9% had marginal deviations in liver test results. Analyses of SLPI and neutrophil lipocalin, a marker of neutrophil activity, indicate compensatory changes in the AAT-deficiency state.