Present increases of anthropogenic CO2 in the atmosphere and surface waters suggest that CO2 related changes in seawater carbonate chemistry will become a general stress factor in aquatic environments. Our knowledge of compensatory mechanisms for systemic acid-base disturbances in cephalopods is limited. This study preliminarily concludes that Sepia officinalis joins a high capacity of acid-base regulation normally found in vertebrates with the ability to maintain or even slightly decrease aerobic energy turnover during acute hypercapnic exposure. In vivo data collected from cannulated specimens illustrated that a metabolic alkalosis, generated by an active accumulation of bicarbonate ions, was sufficient to fully compensate for the respiratory acidosis and buffer haemolymph pH. Monitoring of brain energy status by 31P-NMR spectroscopy found only minor shifts in adenylate ratios. Considering the full compensation of haemolymph pH, it is interesting that brain intracellular pH remained depressed under hypercapnia. This suggests a protective function for lowered brain pHi, where tissue specific metabolic depression could support the maintenance of whole animal energy balance during CO2 stress. Taking into consideration the ability of certain cephalopod species to retain protons and acidic metabolites within the mantle muscle to prevent disturbances of haemolymph homeostasis, further work will focus on measuring the degree of acid-base regulation in muscle tissue. Together these data will allow us to determine if the full level of motoric activity can be conserved in Sepia officinalis during acute hypercapnia.