Background: Understanding the level of patients’ satisfaction with treatment and its determinants have the potential to impact therapeutic management and clinical outcome in chronic conditions such as chronic obstructive pulmonary disease (COPD). Methods: A national, multicenter, longitudinal, observational study of COPD from 20 Italian pulmonary centers to explore patients’ satisfaction to treatment [assessed by the Treatment Satisfaction Questionnaire, 9 items (TSQM-9)] and association with clinical parameters [including dyspnea score, COPD Assessment Test (CAT) score, exacerbation rate], adherence to treatment [Morisky Medication-Taking Adherence Scale (MMAS-4)], illness perception [evaluated by Brief Illness Perception Questionnaire (B-IPQ)] in a 1-year follow up. Results: A total of 401 COPD patients were enrolled [69.4% group B Global Initiative for COPD (GOLD), considering 366 patients with available GOLD 2017 classification at enrollment]. At enrollment, satisfaction with treatment was moderate, being TSQM-9 mean scores for effectiveness 64.2 [95% confidence interval (CI) 62.5–65.9], for convenience 75.8 (95% CI 74.2–77.3), and for global satisfaction 65.7 (95% CI 64.0–67.4). Global satisfaction was negatively associated with disease perception (β = −0.4709, p < 0.0001), and grade of dyspnea (β = −4.2564, p = 0.009). Satisfaction with treatment was lower in patients with poor compared with optimal adherence to treatment (β = −4.5608, p = 0.002). Changes in inhalation regimens during follow up did not modify the satisfaction with treatment. Conclusions: The results of this real-life study showed that the patients’ satisfaction with treatments is only moderate in COPD. A high grade of patients’ satisfaction is associated mainly with a low perception of the disease, high adherence to treatment and lower level of dyspnea. Trial Registration: Clinicaltrials.gov identifier: NCT02689492 The reviews of this paper are available via the supplemental material section.