Background-Peak oxygen uptake (peak V O 2 ) is a strong predictor of mortality and is commonly used in the evaluation of patients for cardiac transplantation. ␤-Blockers reduce mortality in patients with heart failure, without influencing peak V O 2 , raising the possibility that peak V O 2 is no longer suitable as an indicator of prognosis in these patients. Methods and Results-We analyzed prospectively gathered data on 2105 patients referred for cardiopulmonary testing for all-cause mortality and for occurrence of death or transplantation. Patients receiving ␤-blockers were younger, more likely to have coronary disease, and had a greater mean ejection fraction but had a similar peak V O 2 . There were 555 deaths (26%) and 194 (9%) transplants during a median follow-up of 3.5 years. Peak V O 2 was a predictor of mortality irrespective of ␤-blocker use; a decrease of 1 mL · kg Ϫ1 · min Ϫ1 resulted in an adjusted hazard ratio (HR) of 1.13 (95% CI 1.09 to 1.17, PϽ0.0001) in patients not receiving ␤-blockers and 1.27 (95% CI 1.18 to 1.36, PϽ0.0001) in patients receiving ␤-blockers. Similar findings were noted when considering death or transplantation as an end point. ␤-Blocker use was associated with better outcomes until peak V O 2 values became very low (Ϸ10 mL · kg Ϫ1 · min Ϫ1 ), at which level survival rates were equally poor. Conclusion-Peak V O 2 is a determinant of survival in patients in heart failure even in the setting of ␤-blockade. Because of improved survival in patients treated with ␤-blockers, the cut point value of 14 mg · kg Ϫ1 · min Ϫ1 for referral for cardiac transplantation in these patients requires reevaluation, and a lower cut point may be more appropriate.