Background: The rate of lung function decline is one of the most important outcome measures in chronic obstructive pulmonary disease (COPD). Until now, no clinical parameter has been suggested as a predictor of rapid lung function decline other than current smoking and emphysema severity. Objectives: The main purpose of this study was to explore whether exertional desaturation can be a predictor of rapid lung function decline in patients with COPD. Methods: A retrospective analysis was performed of 57 patients with moderate to very severe COPD who underwent 6-minute walk test (6MWT) in a university hospital. Exertional desaturation was defined as nadir oxygen saturation (SpO2) of ≤90% during the 6MWT. Rapid decline was defined as annual rate of decline in forced expiratory volume in 1 second (FEV1) ≥50ml over a 2-year period of follow-up. The patients were divided into rapid decliner (n=26) and non-rapid decliner (n=31). Results: A statistically significant difference was observed between rapid decliner and non-rapid decliner in terms of exertional desaturation (p=0.004). No differences between the groups were observed for age, smoking status, BODE index, and FEV1. Multivariate analysis showed that exertional desaturation was a significant independent predictor of rapid decline in patients with COPD (RR, 5.382; 95% CI, 1.636 to 17.709; p=0.006). Conclusions: This study suggests that exertional desaturation is a predictor of rapid decline in lung function in patients with COPD. 6MWT may be a useful test to predict a rapid lung function decline in COPD.