Purpose: Sputum analysis is important in COPD exacerbation management. We determined whether application of stringent quality control criteria for sputum samples had an impact on culture results. Methods: We analyzed sputum samples of 108 patients during stable COPD and during exacerbations. To all samples quality control standards and culture interpretation rules according to the American Society of Microbiologists (ASM) were applied. Results: In sputum exacerbation samples considered appropriate according to ASM quality standards, criteria for infection (40%) were met more often compared to inappropriate samples (13%) (p < 0.001). The same pattern was observed when applying these rules to sputum samples obtained during stable disease, (50% vs. 18%, p < 0.001). There was no difference in the percentage of infectious cultures obtained during the stable state and exacerbations. Conclusions: Applying stringent quality control criteria to sputum samples can have a profound effect on the labeling of sputum samples as infectious, and therefore on clinical decision making.