RATIONALE: Obesity is a major risk factor towards the development of obstructive sleep apnea, while significant weight loss (both conservatively managed and surgically assisted) has a variable effect upon its severity. Differences in the effect of weight loss on obstructive sleep apnea may be due to underlying craniofacial characteristics. OBJECTIVES: To determine whether craniofacial characteristics can predict OSA treatment response to significant weight loss. METHODS: We analyzed craniofacial measurements from lateral cephalograms performed at baseline on 57 patients enrolled in a previously reported 2-year randomized clinical weight loss trial (laparoscopic adjustable gastric band surgery versus conservatively [dietician and very low calorie diet] treated). Group mean weight loss was ∼ 13% (mean weight loss 131 to 114 kg), with corresponding reduction in mean apnea-hypopnea index (AHI) from 61 to 41 events/h. Computer assisted lateral cephalogram analysis was undertaken by three trained staff blinded to treatment. We analyzed lateral cephalogram and demographic data at baseline (cross-sectional) and change over two years (interventional) in 54 patients. MEASUREMENTS AND MAIN RESULTS: Baseline cross-sectional analysis indicated no cephalometric measurement correlated significantly with baseline AHI when corrected for neck circumference. The percentage change in AHI over 2 years correlated with a shorter menton-gonion distance (i.e., mandibular body length). The % change in AHI correlated with the % weight change (R(2) = 0.25, p < 0.001) and mandibular body length (R(2) = 0.19, p = 0.002). The % change in AHI correlated with combined weight change and mandibular body length (combined R(2) = 0.31, p < 0.001). CONCLUSIONS: Weight loss as a therapeutic option for severe OSA with severe obesity may be predicted by shorter mandibular body length as measured by lateral cephalometry.