Background Sleep-disordered breathing, particularly central sleep apnea (CSA), is highly prevalent in heart failure (HF) and an independent prognostic marker. We assessed the hypothesis that an increased hypoxemic burden during sleep may have greater prognostic value than the frequency of apneic and hypopneic episodes. Methods and Results We prospectively conducted overnight cardiorespiratory polygraphy on consecutive HF patients referred to our hospital between 2008 and 2011. We studied CSA defined by an apnea-hypopnea index (AHI) of ≥5 events/h, whereby >75% of all events were central in origin. We determined the AHI, proportion of the sleep time with an SpO2<90% (T90%), and percent of the recording time that 4% desaturation events occurred (4%POD). We studied 112 HF patients with either systolic or diastolic dysfunction. During a follow-up period of 37±25 months, 32 patients (29%) died. Non-survivors had a higher 4%POD compared to survivors (11±6.4 vs. 19±13%, p=0.001), but did not differ significantly regarding the AHI and T90% compared to survivors. An adjusted logistic regression analysis revealed that the 4%POD was the best independent predictor of mortality. Conclusion The 4%POD, a novel metric for the nocturnal hypoxemic burden, is an independent prognostic marker in HF patients affected by CSA.