The role of skeletal muscle metaboreceptive afferents in human cardiorespiratory control can be examined using post exercise circulatory occlusion (PECO)( Alam and Smirk 1937, Coote et al 1971, Rowell 1976). We have shown that PECO produces ventilatory responses in humans, but only during concurrent hypercapnia (Bruce and White 2012). This is not due to local muscle hypercapnia as the effect is absent if only the active muscle, not the systemic circulation, is exposed to elevated arterial carbon dioxide. We now aim to determine the extent to which the ventilatory response to hypercapnia in PECO is due to an effect mediated by central or peripheral chemoreception. This was achieved by comparing ventilatory and cardiovascular responses to PECO during normoxic hypercapnia (5% carbon dioxide in air) with those seen during hyperoxic hypercapnia (5% carbon dioxide, 95% oxygen) which is expected to diminish markedly, peripheral chemoreflex activation (Dejours 1962). With Ethical Committee approval, 10 males seated in an dynamometer performed the following protocol. During inhalation of the normoxic hypercapnic gas mixture a cuff was inflated to 200mmHg around the right thigh. Continuing to breathe this mixture subjects performed a sustained isometric contraction of their right plantarflexors for 1.5 min at 50% MVC, followed by PECO for 3.5min. At this point with continued PECO subjects were switched to inhale the hyperoxic hypercapnic mixture for a further 2 minutes after which time they reverted to the normoxic hypercapnic mixture for 2 more minutes. The thigh cuff was then deflated and after 3 more minutes of normoxic hypercapnia the subjects returned to breathing room air. We found that PECO maintained blood pressure at exercising levels, suggesting activation of metaboreceptive afferents and as expected ventilation was maintained at exercising levels during normoxic hypercapnia (~6 l.min-1). The switch to hyperoxic hypercapnia had no effect on this ventilatory response which was sustained until thigh cuff deflation. These results suggest that ventilatory responses induced by muscle metaboreceptive afferent feedback during concurrent hypercapnia are primarily driven by central chemoreception.