Background: Automatic continuous positive airway pressure (auto-CPAP) machines differ mainly in algorithms used for respiratory event detection and pressure control. The auto-CPAP machines operated by novel algorithms are expected to have better performance than the earlier ones in the treatment of obstructive sleep apnea syndrome (OSAS). Objectives: The purpose of this study was to determine the therapeutic characteristics between two different auto-CPAP devices, i.e., the third-generation flow-based (f-APAP) and the second-generation vibration-based (v-APAP) machines, during the first night treatment of OSAS. Methods: We retrospectively reviewed the polysomnography (PSG) recordings of 43 OSAS patients who were initially performed an overnight diagnostic PSG to confirm the disease and afterwards received the first night auto-CPAP treatment with using either the f-APAP ( n = 22) or v-APAP ( n = 21) device under another PSG evaluation. Results: There were 13.6% and 61.9% patients who remained a residual apnea/hypopnea index more than 5 during the f-APAP and v-APAP application, respectively ( P < 0.005). The f-APAP was more effective than the v-APAP in reducing apnea/hypopnea index ( P = 0.003), hypopnea index ( P = 0.023) and apnea index ( P = 0.007), improving the lowest oxygen saturation index ( P = 0.007) and shortening stage 1 sleep ( P = 0.016). However, the f-APAP was less sufficient than the v-APAP in reducing arousal/awakening index ( P = 0.02). Conclusion: These findings suggest that the f-APAP works better than the v-APAP in abolishing breathing abnormities in the treatment of OSAS; however, the f-APAP device might still have some potential limitations in the clinical application.