Introduction Previous reports demonstrated adiponectin has anti-atherosclerotic properties. Obstructive sleep apnea hypopnea syndrome (OSAHS) is reported to exacerbate atherosclerotic diseases. We investigated nocturnal alternation of serum adiponectin levels before sleep and after wake-up in OSAHS patients, and the effect of sustained hypoxia on adiponectin in-vivo and in-vitro. Materials and Methods We measured serum adiponectin concentrations in 75 OSAHS patients and 18 controls before sleep and after wake-up, and examined the effect of one-night nasal continuous positive airway pressure (nCPAP) on adiponectin in 24 severe OSAHS patients. We investigated the effects of hypoxia on adiponectin in mice and cultured adipocytes using sustained hypoxia model. Results Circulating adiponectin levels before sleep and after wake-up were lower in severe OSAHS patients than in controls (before sleep; 5.9±2.9 versus 8.8±5.6 µg/mL, P<0.05, after wake-up; 5.2±2.6 µg/mL versus 8.5±5.5 µg/mL, mean±SD, P<0.01, respectively). Serum adiponectin levels diminished significantly during sleep in severe OSAHS patients (P<0.0001), but one-night nCPAP improved the drop in serum adiponectin levels (-18.4±13.4% versus -10.4±12.4%, P<0.05). In C57BL/6J mice and 3T3-L1 adipocytes, hypoxic exposure decreased adiponectin concentrations by inhibiting adiponectin regulatory mechanisms at secretion and transcriptional levels. Conclusions The present study demonstrated nocturnal reduction in circulating adiponectin levels in severe OSAHS. Our experimental studies showed hypoxic stress induced adiponectin dysregulation at transcriptional and post-transcriptional levels. Hypoxic stress is, at least partly, responsible for the reduction of serum adiponectin in severe OSAHS. Nocturnal reduction in adiponectin in severe OSAHS may be an important risk of cardiovascular events or other OSAHS-related diseases during sleep.