Previous studies have suggested that during non-rapid eye movement (NREM) sleep, neither large short-duration resistive loads nor sustained normoxic hypercapnia alone leads to increased genioglossus muscle activation. However, in normal individuals during stable NREM sleep, genioglossus activity rises above baseline as PCO2 rises and airway resistance increases. We therefore hypothesized that combinations of chemical (PCO2, PO2) and mechanical stimuli during NREM sleep would lead to increased genioglossal activation. We studied 15 normal subjects (9 males, 6 females) during stable NREM sleep, measuring genioglossus electromyogram, epiglottic/choanal pressure, and airflow under six conditions: (1) baseline, (2) inspiratory resistive loading (-5 to -15 cm H2O/ L/second), (3) increased PCO2 (5-10 mm Hg above baseline), (4) combined resistive loading and increased PCO2, (5 ) hypoxia (SaO2 80-85%), and (6 ) combined hypoxia/inspiratory resistive loading. Only the combined condition of hypercapnia and resistive loading led to significantly increased genioglossal activation, 3.91 +/- 0.77% to 9.64 +/- 1.96% of maximum. These data suggest that the genioglossus muscle is less responsive to either chemical stimuli (hypercapnia, hypoxia) or inspiratory resistive loading alone during NREM sleep at the degrees tested. When hypercapnia is combined with resistive loading, the muscle does respond. However, the possibility that higher levels of PCO2 or greater resistive loading alone could activate the muscle cannot be excluded.