Background: It has been recognized that mandibular advancement splint (MAS) treatment is effective in some, but not all, patients with obstructive sleep apnea (OSA). Hence there is a need for a simple and reliable clinical tool to assist in the differentiation of treatment responses. We hypothesized that abnormalities of flow–volume curves, together with other clinical variables, may have clinical utility in the prediction of MAS treatment outcome. Methods: Fifty-four patients with known OSA underwent MAS treatment. Expiratory and inspiratory flow–volume curves were measured in the erect and supine positions to derive midinspiratory flow (MIF₅₀) and the ratio of expiratory to inspiratory flow at 50% of vital capacity (MEF₅₀:MIF₅₀). Multivariable logistic regression was performed to identify additional significant clinical variables in the prediction of treatment outcome. Results: The mean (± SD) apnea–hypopnea index (AHI) in 35 responders was significantly reduced from 28.9 ± 13.7 to 6.7 ± 5.8/hour (p < 0.001). In 19 nonresponders there was no significant change in AHI. MIF50 was lower (6.04 ± 1.80 vs. 6.88 ± 1.08 L/second; p = 0.035) and the MEF₅₀:MIF₅₀ ratio was higher (0.82 ± 0.23 vs. 0.61 ± 0.15; p = 0.001) in responders than nonresponders. Logistic regression analysis revealed that the MEF₅₀:MIF₅₀ ratio was the most important predictive factor for MAS treatment outcome, but that body mass index, age, and baseline AHI were also contributory. Conclusions: These data suggest that flow–volume curves, in combination with other factors such as body mass index, age, and baseline AHI, may have a useful clinical role in the prediction of treatment outcome with MAS.