Purpose: Evaluate the effectiveness of the head-of-bed elevation position (HOBE) with a 30° elevation of the head and trunk, in improving obstruction of the upper airways in obstructive sleep apnea (OSA) patients. A prospective trial simultaneously performing drug-induced sleep endoscopy (DISE) and polysomnography (PSG) tests was performed. Methods: Forty-five patients were included in the prospective study protocol. All patients enrolled in the study and underwent the following evaluations: (1) a drug-induced sleep endoscopy, with an evaluation of obstructions and collapse of the upper airways at 0° and in a HOBE position, with head and trunk elevation of 30°; (2) an overnight PSG assessment in the hospital with head and trunk elevation from 0° to 30° during the night; (3) a questionnaire to evaluate the feedback of patients to sleeping with head-of-bed elevation. Results: Velum (V) and oropharynx lateral wall (O) collapses were reduced in the 30° up position. There were no statistical differences that emerged in the obstruction of the tongue base and epiglottis between the 0° position and the 30° up position (p > 0.05). The average AHI score changed from 23.8 ± 13.3 (0° supine position) to 17.7 ± 12.4 (HOBE position), with a statistical difference (p = 0.03); the same statistical difference emerged in the percentage of apneas that decreased from 55 ± 28.1 to 44 ± 25.8 (p = 0.05). Conclusions: By adopting the HOBE position with 30° elevation of the head and trunk, it is possible to obtain a reduction of upper airways collapses and an improvement of apnea/hypopnea events and nightly respiratory outcomes.