In this study, we aimed to assess the ventilatory and cardiovascular responses to the combined activation of the muscle metaboreflex and the ventilatory chemoreflex, achieved by postexercise circulatory occlusion (PECO) and euoxic hypercapnia (end-tidal partial pressure of CO2 7 mmHg above normal), respectively. Eleven healthy subjects (4 women and 7 men; 29 +/- 4.4 years old; mean +/- s.d.) undertook the following four trials, in random order: 2 min of isometric handgrip exercise followed by 2 min of PECO with hypercapnia; 2 min of isometric handgrip exercise followed by 2 min of PECO while breathing room air; 4 min of rest with hypercapnia; and 4 min of rest while breathing room air. Ventilation was significantly increased during exercise in both the hypercapnic (+3.17 +/- 0.82 l min-1) and the room air breathing trials (+2.90 +/- 0.26 l min-1; all P <0.05). During PECO, ventilation returned to pre-exercise levels when breathing room air (+0.52 +/- 0.37 l min-1; P > 0.05), but it remained elevated during hypercapnia (+3.77 +/- 0.23 l min-1; P <0.05). The results indicate that the muscle metaboreflex stimulates ventilation with concurrent chemoreflex activation. These findings have implications for disease states where effort intolerance and breathlessness are linked.