Rationale: Hypoglossal nerve stimulation (HGNS) recruits lingual muscles, reduces pharyngeal collapsibility, and treats sleep apnea. Objectives: We hypothesized that graded increases in HGNS relieve pharyngeal obstruction progressively during sleep. Methods: Responses were examined in 30 patients with sleep apnea who were implanted with an HGNS system. Current (milliampere) was increased stepwise during non-REM sleep. Frequency and pulse width were fixed. At each current level, stimulation was applied on alternating breaths, and responses in maximal inspiratory airflow (V I max) and inspiratory airflow limitation (IFL) were assessed. Pharyngeal responses to HGNS were characterized by the current levels at which V I max first increased and peaked (flow capture and peak flow thresholds), and by the V I max increase from flow capture to peak (DV I max). Measurements and Main Results: HGNS produced linear increases in V I max from unstimulated levels at flow capture to peak flow thresholds (215 6 21 to 509 6 37 ml/s; mean 6 SE; P , 0.001) with increasing current from 1.05 6 0.09 to 1.46 6 0.11 mA. V I max increased in all patients and IFL was abolished in 57% of patients (non-IFL subgroup). In the non-IFL compared with IFL subgroup, the flow response slope was greater (1241 6 199 vs. 674 6 166 ml/s/mA; P , 0.05) and the stimulation amplitude at peak flow was lower (1.23 6 0.10 vs. 1.80 6 0.20 mA; P , 0.05) without differences in peak flow. Conclusions: HGNS produced marked dose-related increases in airflow without arousing patients from sleep. Increases in airflow were of sufficient magnitude to eliminate IFL in most patients and IFL and non-IFL subgroups achieved normal or near-normal levels of flow, suggesting potential HGNS efficacy across a broad range of sleep apnea severity.Keywords: obstructive sleep apnea; electrical hypoglossal nerve stimulation; pharynx; upper airway; titration Obstructive sleep apnea is characterized by recurrent episodes of upper airway obstruction during sleep (1). Airflow obstruction is thought to result from decreases in pharyngeal neuromuscular activity at sleep onset (2). These episodes lead to intermittent hypoxemia and recurrent arousals from sleep, accounting for the long-term neurocognitive (3, 4), metabolic (5), and cardiovascular (6) sequelae of this disorder. Nasal continuous positive airway pressure remains the mainstay of treatment for moderate to severe obstructive sleep apnea (7). Difficulties adhering to therapy can limit its effectiveness in the home setting (8, 9), and alternatives have been generally less effective in relieving upper airway obstruction during sleep (10-12).Hypoglossal nerve stimulation (HGNS) has been piloted as treatment for obstructive sleep apnea (13). Implantable HGNS systems have been developed to stimulate the hypoglossal nerve during inspiration, and recruit the lingual musculature, leading to decreases in pharyngeal collapsibility during sleep (14-17). Motor activity protrudes the tongue, and mitigates airflow obstruction during sleep (18,19)....