Rationale: Cardiovascular drugs may improve survival in chronic obstructive pulmonary disease (COPD). However, previous studies did not account for major sources of bias, and drug effects have not been evaluated in severe COPD. Objectives: To estimate the time-dependent effects of cardiovascular drugs on survival in oxygen-dependent COPD, accounting for immortal and immeasurable time bias. Methods: Prospective national study of patients starting long-term oxygen therapy for COPD in Sweden between 1 October 2005 and 30 June 2009. Effects on mortality were estimated using extended Cox regression adjusted for age, sex, Pa-O2, Pa-CO2, World Health Organization performance status, body mass index, comorbidity, and concomitant medications. Immortal and immeasurable time bias was addressed by analyzing all medications as time-dependent variables and accounting for hospitalized time, respectively. Measurements and Main Results: Time-dependent effects of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, antiplatelet drugs, beta-blockers, and statins on all-cause mortality were measured. Of the 2,249 included patients, 1,129 (50%) died under observation. No patient was lost to follow-up. The adjusted time-dependent model was compatible with reduced mortality for antiplatelet drugs (hazard ratio [HR], 0.86; 95% CI, 0.75-0.99; P = 0.030) and trends for angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (HR, 0.90; 95% CI, 0.79-1.04; P = 0.166) and statins (HR, 0.86; 95% CI, 0.72-1.03; P = 0.105), whereas beta-blockers increased mortality (HR, 1.19; 95% CI, 1.04-1.37; P = 0.010). Conclusions: This study supports that antiplatelet drugs improve surviva