Although inhaled therapy reduces exacerbations among COPD patients, the effectiveness of providing inhaled treatment per recent risk-stratification models remains unclear.Are inhaled regimens that align with the 2017 Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy associated with clinically important outcomes?and Methods: We conducted secondary analyses of Long-term Oxygen Treatment Trial data. The trial enrolled COPD patients with moderate resting or exertional hypoxemia between 2009-2015. Our exposure was the patient-reported inhaled regimen at enrollment, categorized as either aligning with, undertreating, or potentially overtreating per the 2017 GOLD strategy. Our primary composite outcome was time-to death or first hospitalization for COPD. Additional outcomes included individual components of the composite outcome and time-to first exacerbation. We generated multivariable Cox proportional-hazard models across strata of GOLD-predicted exacerbation risk (high vs low) to estimate between-group hazard ratios for time-to-event outcomes. We adjusted models a priori for potential confounders, clustered by site.The trial enrolled 738 patients; 73.4% were male with mean age 68.8 years. 571 patients (77.4%) were low-risk for future exacerbations. 233 patients (31.6%) reported regimens aligning with GOLD recommendations; most regimens (54.1%) potentially overtreated. During 2.3-year median follow-up, 332 patients (44.9%) experienced the composite outcome. We found no difference in time-to composite outcome or death among patients reporting regimens aligning with recommendations compared to undertreated patients. Among low-risk patients, potential overtreatment was associated with higher exacerbation risk (HR 1.42, 95% CI: 1.09,1.87) while inhaled corticosteroid treatment was associated with 64% higher risk of pneumonia (IRR 1.64, 95% CI: 1.01, 2.66).Among COPD patients with moderate hypoxemia, we found no difference in clinical outcomes between inhaled regimens aligning with the 2017 GOLD strategy compared to those that undertreated. These findings suggest the need to reevaluate the effectiveness of risk stratification model-based inhaled treatment strategies.