Emphysema distribution is associated with COPD. It is however unknown whether CT-quantified emphysema distribution (upper/lower lobe) is associated with lung function decline in heavy (former) smokers.587 male participants underwent lung CT-scanning and pulmonary function testing at baseline and after a median (interquartile range) follow-up of 2.9 (2.8-3.0) years. The lungs were automatically segmented based on anatomically defined lung lobes. Severity of emphysema was automatically quantified per anatomical lung lobe and was expressed as the 15(th) percentile (HU-point below which 15\% of the low attenuation voxels are distributed (Perc15)). The CT-quantified emphysema distribution was based on principal component analysis. Linear mixed models were used to assess the association of emphysema distribution with FEV1/FVC, FEV1 and FVC-decline.Mean (SD) age was 60.2 (5.4) years, mean baseline FEV1/FVC was 71.6 (9.0) \% and overall mean Perc15 was -908.5 (20.9) HU. Participants with upper lobe predominant CT-quantified emphysema had a lower FEV1/FVC, FEV1 and FVC after follow-up compared to participants with lower lobe predominant CT-quantified emphysema (p=0.001), independent of the total extent of CT-quantified emphysema.Heavy (former) smokers with upper lobe predominant CT-quantified emphysema have a more rapid decrease in lung function than those with lower lobe predominant CT-quantified emphysema.