Background. Nocturnal sustained hypoxia during sleeping time has been reported in severe obesity, but no information regarding the cardiac molecular mechanism in the coexistence of nocturnal sustained hypoxia and obesity is available. This study evaluates whether the coexistence of nocturnal sustained hypoxia and obesity will increase cardiac Fas death receptor and mitochondrial dependent apoptotic pathway. Methods. Thirty-two lean and thirty-two obese 5-to-6-month-old rats were studied and assigned to one of four subgroups: normoxia lean(NL), normoxia obese(NO), hypoxia lean (HL,12%O₂ for 8 hr and 21%O₂ 16hr/day,1 week), and hypoxia obese(HO). The heart weight index, tail cuff plethysmography, echocardiography, H&Estaining, TUNELassays, Western blotting and reverse transcription polymerase chain reaction(RT-PCR) were performed. Results. SBP and DBP in HO were higher than NL, and fractional shortening in HO was reduced compared to others. The whole heart weight, the left ventricular weight, the abnormal myocardial architecture, and TUNEL-positive apoptotic cells, as well as the activity of cardiac Fas receptor-and-mitochondrial- dependent apoptotic pathway, were significantly increased in obese group or nocturnal sustained hypoxia group, and were further increased when there was coexistent obesity and nocturnal sustained hypoxia, the evidence for which is based on decreases in an anti-apoptotic protein Bcl2 level and Bid and increases in Fas, FADD, pro-apoptotic Bad, BNIP3, cytosolic cytochrome c, activated caspase-8, activated caspase-9 and activated caspase-3. Conclusions. The cardiac Fas receptor- and mitochondrial-dependent apoptotic pathways were more activated in coexistent obesity and nocturnal sustained hypoxia, which may represent one possible apoptotic mechanism for the development of heart failure in obesity with nocturnal sustained hypoxia.