Sputum induction (SI) is considered to be a safe tool for assessing airway inflammation in stable patients with COPD, but little is known about its safety during exacerbations. We therefore assessed the safety of SI during COPD exacerbations. SI data from 44 COPD patients were assessed both in the stable phase and during exacerbation. The median FEV1 for the stable phase and exacerbation were 61% predicted (interquartile range [IQR], 49 to 74% predicted) and 51% predicted (IQR, 45 to 60% predicted), respectively. The median decrease in FEV1 with SI during an exacerbation was 0.27 L (IQR, 0.17 to 0.40 L) vs 0.28 L (IQR, 0.22 to 0.44 L) during the stable phase (p = 0.03). The patients experienced the associated dyspnea well; no other adverse events occurred. All FEV1 values returned to within 90% of their initial value within 30 min. A larger decrease in FEV1 due to SI during an exacerbation was associated with the following parameters in the stable phase of disease: lower total sputum cell count (r = −0.37; p = 0.01); higher percentage of eosinophils (r = 0.33; p = 0.04); and a larger decrease in FEV1 after SI (r = 0.39; p = 0.03). In a multivariate analysis, the only independent association was with the larger decrease in FEV1 in the stable phase. We concluded that SI can be safely carried out in patients with mild-to-moderate COPD who experience an exacerbation, and this occurs with no greater risk than in stable patients with COPD.