RATIONALE: To date, no studies have quantitatively evaluated chronic obstructive pulmonary disease (COPD) longitudinally using hyperpolarized helium-3 () magnetic resonance imaging (MRI). OBJECTIVES: To evaluate COPD longitudinally using hyperpolarized MRI and to determine correlations between the changes in MRI ventilation defect volume (VDV), apparent diffusion coefficients (ADC) and changes in pulmonary function. METHODS: Hyperpolarized MRI, spirometry and plethysmography were performed in 15 COPD ex-smokers ( stage II and stage III/IV COPD) at baseline and 26±2 months later. MRI ADC values were calculated from MRI diffusion-weighted images and VDV were generated after manual segmentation of MRI spin-density images. MEASUREMENTS AND MAIN RESULTS: At follow-up, COPD subjects showed significant increases in MRI CS VDV (), WL VDV (), as well as ADC () and no significant change in (). There was a significant correlation between changes in and changes in CS VDV (, ), however no significant correlations between smoking history (years non-smoker at baseline) and changes in MRI measurements or was found. CONCLUSIONS: For COPD ex-smokers, MRI VDV and ADC measurements worsened significantly but there was no significant change in FEV1, suggesting higher sensitivity of hyperpolarized MRI to COPD changes over short periods of time.