FEV₁ is fundamental to the diagnosis and staging of chronic obstructive pulmonary disease. In emphysema, airflow obstruction usually coexists with impairment of gas exchange, but discordance is not infrequent. We hypothesized that variations in the distribution of emphysema would be associated with functional differences and therefore account for discordant physiology. We used quantitative computed tomography to assess emphysema severity and distribution in 119 subjects with α1-antitrypsin deficiency (PiZ phenotype) and grouped them according to distribution pattern. In the 102 subjects with emphysema, 65 had a predominantly basal pattern (“basal”), but 37 (36%) had greater involvement of the upper regions (“apical”). Subjects from each group were matched for total volume of emphysema and age, and matched pairs analysis was used to relate emphysema distribution to clinical phenotype. Basal distribution was associated with greater impairment of FEV₁ (mean difference, 9.9% predicted; 95% confidence interval, 3.8 to 16.0; p = 0.002) but less impairment of gas exchange (Pa_O2 mean difference, 0.5 kPa, 0.03 to 0.1; p = 0.016) and alveolar–arterial oxygen gradient (mean difference, 0.7 kPa; 0.2 to 1.2; p = 0.007) than the apical distribution. Emphysema distribution correlated with physiologic discordance (r = −0.409, p < 0.001). The use of single physiologic parameters as a surrogate measure of emphysema severity may introduce systematic bias in the staging of subjects with emphysema.