RATIONALE: Increasing awareness of the prevalence and significance of Preserved Ratio Impaired Spirometry (PRISm), alternatively known as restrictive or Global Initiative for Chronic Obstructive Lung Disease (GOLD)-unclassified spirometry, has expanded the body of knowledge on cross-sectional risk factors. However, longitudinal studies of PRISm remain limited. OBJECTIVES: To examine longitudinal patterns of change in lung function, radiographic characteristics, and mortality of current and former smokers with PRISm. METHODS: Current and former smokers, aged 45 to 80 years, were enrolled in COPDGene (phase 1, 2008-2011) and returned for a 5-year follow-up (phase 2, 2012-2016). Subjects completed questionnaires, spirometry, chest computed tomography scans, and 6-minute-walk tests at both study visits. Baseline characteristics, longitudinal change in lung function, and mortality were assessed by post-bronchodilator lung function categories: PRISm (FEV1/FVC < 0.7 and FEV1 < 80%), GOLD0 (FEV1/FVC > 0.7 and FEV1 > 80%), and GOLD1-4 (FEV1/FVC < 0.7). MEASUREMENTS AND MAIN RESULTS: Although the prevalence of PRISm was consistent (12.4-12.5%) at phases 1 and 2, subjects with PRISm exhibited substantial rates of transition to and from other lung function categories. Among subjects with PRISm at phase 1, 22.2% transitioned to GOLD0 and 25.1% progressed to GOLD1-4 at phase 2. Subjects with PRISm at both phase 1 and phase 2 had reduced rates of FEV1 decline (-27.3 ± 42.1 vs. -33.0 ± 41.7 ml/yr) and comparable proportions of normal computed tomography scans (51% vs. 52.7%) relative to subjects with stable GOLD0 spirometry. In contrast, incident PRISm exhibited accelerated rates of lung function decline. Subjects with PRISm at phase 1 had higher mortality rates relative to GOLD0 and lower rates relative to the GOLD1-4 group. CONCLUSIONS: PRISm is highly prevalent, is associated with increased mortality, and represents a transitional state for significant subgroups of subjects. Additional studies to characterize longitudinal progression in PRISm are warranted.