What is the central question of this study? What is the relationship between the level of systemic hypercapnia and the magnitude of the additional hyperpnoea produced in response to a standardized level of muscle metaboreflex activation? What is the main finding and its importance? When a standardized activation of the muscle metaboreflex was combined with exposure to increasing levels of hypercapnia, the hyperpnoea this caused increased linearly. The concept of a synergistic interaction between the muscle metaboreflex and the central chemoreflex in humans is supported by this finding. ⋯ Ventilation increases during muscle metaboreflex activation when postexercise circulatory occlusion (PECO) traps metabolites in resting human muscle, but only in conditions of concurrent systemic hypercapnia. We hypothesize that a linear relationship exists between the level of hypercapnia and the magnitude of the additional hyperpnoea produced in response to a standardized level of muscle metaboreflex activation. Fifteen male subjects performed four trials, in which the end-tidal partial pressure of carbon dioxide ( PET,CO2 ) was elevated by 1, 3, 7 or 10 mmHg above resting values using a dynamic end-tidal forcing system. In each trial, subjects were seated in an isometric dynamometer designed to measure ankle plantar flexor force. Rest for 2 min in room air was followed by 15 min of exposure to one of the four levels of hypercapnia, at which 5 min further rest was followed by 2 min of sustained isometric calf muscle contraction at 50% of predetermined maximal voluntary strength. Immediately before cessation of exercise, a cuff around the upper leg was inflated to a suprasystolic pressure to cause PECO for 3 min, before its deflation and a further 5 min of rest, concluding exposure to hypercapnia. The PECO consistently elevated mean arterial blood pressure by ∼10 mmHg in all trials, indicating similar levels of metaboreflex activation. Increased ventilation during PECO was related to PET,CO2 as described by the following linear regression equation: Change in minute ventilation (l min-1 ) = 0.85 × PET,CO2 (mmHg) + 0.80 (l min-1 ). This finding supports our hypothesis and furthers the idea of a synergistic interaction between muscle metaboreflex activation and central chemoreflex stimulation.