Purpose The 6-min walk test (6MWT) is a useful tool to assess the physiologic function in patients with chronic obstructive pulmonary disease (COPD). The recent study showed that patients with COPD with oxygen desaturation during the 6MWT had an increased risk of exacerbation and death compared with those without oxygen desaturation. This study aimed to explore the potential risk factors for exercise-induced desaturation (EID) in patients with COPD. Patients and Methods Adult patients with COPD were enrolled from the Chang Gung Research Database between January 2013 and January 2017. Age, sex, body mass index, underlying diseases, medications, and results of the pulmonary function tests and 6MWT were retrospectively collected and analyzed. Results Among 1768 patients with COPD, 932 (52.7%) had oxygen desaturation, and the other 836 (47.3%) had no desaturation during the 6MWT. The patients with EID had a shorter 6-min walk distance than those without desaturation (352.08±120.29 vs 426.56±112.56, p<0.0001). In the multivariate logistic regression analysis, older age, female sex, lower forced expiratory volume in 1 s, and comorbidity with atrial fibrillation (AF) were associated with oxygen desaturation during the 6MWT. Patients with EID had higher exacerbation frequency than those without desaturation in the 1-year follow-up period (0.59±1.50 vs 0.34±1.26, p<0.0001). Patients with COPD with AF also had a higher rate of exacerbation requiring emergency department visit or hospitalization in the 1-year follow-up. Conclusion This study demonstrates that older age, low FEV1, and female sex are risk factors for EID. Desaturation during 6MWT is related to frequent acute exacerbation of COPD in the 1-year follow-up.