Obliterative bronchiolitis (OB) is the first cause of death of long-term survivors of lung transplantation. The diagnosis is based on pathology and/or on an irreversible decrease in forced expiratory volume in 1 s (FEV(1)) below 80% of the best postoperative value. We tested whether indexes of ventilation distribution may provide evidence of OB before conventional pulmonary function tests (PFTs). Fifty-seven patients with heart-lung (n = 47) or double-lung (n = 10) transplantation were monitored with conventional PFTs and measurements of the slope of the alveolar plateau for He (S(He)), SF(6) (S(SF6)), and N(2) (S(N2)) obtained during single-breath washouts. The date at which a functional variable showed an irreversible change outside the 97.5% confidence interval was compared with the date at which a greater than 20% fall in FEV(1) was observed. A total of 1,929 tests (median, 30 tests per patient) were performed during the 1,215 d (range, 164-2,829 d) of follow-up. Eighteen patients showed an irreversible and greater than 20% fall in FEV(1) during the course of the study. This alteration was preceded by a rise in S(He) in 17 patients and by a rise in S(N2) in 16 patients, which indicated a more heterogeneous ventilation. The median time interval between the change in S(He) and S(N2) and the 20% decrease in FEV(1) was 356 and 168 d, respectively, with seven patients showing an interval of 18 mo or more. Conventional PFTs, including midexpiratory flow rates, deteriorated after indexes of ventilation distribution. Thirty-nine patients did not show any significant and irreversible alteration in conventional PFTs over the study period; only seven of these patients developed significant alterations in ventilation distribution. We conclude that measurements of ventilation distribution detect posttransplant OB much earlier than conventional PFTs.