--- - |2+ Key points Chronic hypercapnia per se has distinct effects on the mechanisms regulating steady‐state ventilation and the CO2/H+ chemoreflex. Chronic hypercapnia leads to sustained hyperpnoea that exceeds predicted ventilation based upon the CO2/H+ chemoreflex. There is an integrative ventilatory, cardiovascular and metabolic physiological response to chronic hypercapnia. Chronic hypercapnia leads to deterioration of cognitive function. Abstract Respiratory diseases such as chronic obstructive pulmonary disease (COPD) often lead to chronic hypercapnia which may exacerbate progression of the disease, increase risk of mortality and contribute to comorbidities such as cognitive dysfunction. Determining the contribution of hypercapnia per se to adaptations in ventilation and cognitive dysfunction within this patient population is complicated by the presence of multiple comorbidities. Herein, we sought to determine the role of chronic hypercapnia per se on the temporal pattern of ventilation and the ventilatory CO2/H+ chemoreflex by exposing healthy goats to either room air or an elevated inspired CO2 (InCO2) of 6% for 30 days. A second objective was to determine whether chronic hypercapnia per se contributes to cognitive dysfunction. During 30 days of exposure to 6% InCO2, steady‐state (SS) ventilation (I) initially increased to 335% of control, and then within 1–5 days decreased and stabilized at ∼230% of control. There was an initial respiratory acidosis that was partially mitigated over time due to increased arterial [HCO3−]. There was a transient decrease in the ventilatory CO2/H+ chemoreflex, followed by return to pre‐exposure levels. The SS I during chronic hypercapnia was greater than predicted from the acute CO2/H+ chemoreflex, suggesting separate mechanisms regulating SS I and the chemoreflex. Finally, as assessed by a shape discrimination test, we found a sustained decrease in cognitive function during chronic hypercapnia. We conclude that chronic hypercapnia per se results in: (1) a disconnect between SS I and the CO2/H+ chemoreflex, and (2) deterioration of cognitive function. - 'The Journal of Physiology, Volume 596, Issue 22, Page 5343-5363, 15 November 2018. '