Background: Obstructive sleep apnoea (OSA) is commonly associated with obesity and can be improved by weight loss. Changes in upper airway size related to regional fat loss may mediate the improvement in OSA. This study aimed to assess changes in upper airway size and regional facial and abdominal fat with weight loss and their association with OSA improvement. Methods: Middle-aged obese men with moderate-tosevere OSA underwent a 24-week sibutramine-assisted weight loss trial. Polysomnography and CT of the head and neck were performed at baseline and 24 weeks. The upper airway lumen and facial and parapharyngeal fat were measured with image analysis software. Results: Post-intervention there was a significant reduction in weight (-7.8±4.2 kg, p<0.001) and apnoea-hypopnoea index (AHI) (-15.9±20.5 events/h, p<0.001). Velopharyngeal airway volume significantly increased from baseline (5.3±0.4 to 6.3±0.3 cm3, p<0.01) and facial and paraphayngeal fat volume significantly reduced. A reduction in upper airway length was associated with improvement in AHI (r=0.385, p=0.005). The variance in AHI improvement was best explained by changes in upper airway length and visceral abdominal fat (R2=0.31, p=0.004). Conclusions: Weight loss increases velopharyngeal airway volume, but changes in upper airway length appear to have a greater influence on the reduction in apnoea frequency. Inter-individual variability in the effects of weight loss on OSA severity cannot be explained in terms of changes in upper airway structure and local fat deposition alone.