Sensory neurons are able to detect tissue ischaemia and both transmit information to the brainstem as well as release local vasoactive mediators. Their ability to sense tissue ischaemia is assumed to be primarily mediated through proton sensing ion channels, lack of oxygen however may also affect sensory neuron function. In this study we investigated the effects of anoxia on isolated capsaicin sensitive neurons from rat nodose ganglion. Acute anoxia triggered a reversible increase in [Ca 2+ ] i that was mainly due to Ca 2+ -efflux from FCCP sensitive stores and from caffeine and CPA sensitive ER stores. Prolonged anoxia resulted in complete depletion of ER Ca 2+ -stores. Mitochondria were partially depolarised by acute anoxia but mitochondrial Ca 2+ -uptake/buffering during voltage-gated Ca 2+ -influx was unaffected. The process of Ca 2+ -release from mitochondria and cytosolic Ca 2+ -clearance following Ca 2+ influx was however significantly slowed. Anoxia was also found to inhibit SERCA activity and, to a lesser extent, PMCA activity. Hence, anoxia has multiple influences on [Ca 2+ ] i homeostasis in vagal afferent neurons, including depression of ATP-driven Ca 2+ -pumps, modulation of the kinetics of mitochondrial Ca 2+ buffering/release and Ca 2+ -release from, and depletion of, internal Ca 2+ -stores. These effects are likely to influence sensory neuronal function during ischaemia.