We examined the immunohistochemical expression of caspase-3 (CASP3), active caspase-3 and TUNEL in the normal piglet brainstem at 13-14 days of age and evaluated the effects of exposure to 2 vs. 4 days of intermittent hypercapnic hypoxia (IHH) on their expression. Eight nuclei from the level of the caudal medulla were studied. In control piglets, CASP3 was present in approximately 45% of neurons while active caspase-3 and TUNEL were present in approximately 5%, indicating that approximately half the neuronal population of the piglet medulla express caspase-3 in a latent state and that only approximately 5% undergo 'normal' programmed cell death. After 2 days of IHH, CASP3 increased in the nucleus of the solitary tract (NTS), gracile and cuneate nuclei (P<0.05 for all). Active caspase-3 increased in the dorsal motor nucleus of the vagus (DMNV) (P<0.05) but decreased in the lateral reticular nucleus (LRt) (P<0.05), while TUNEL increased in both the DMNV and LRt (P<0.05 for both). After 4 days of IHH, CASP3 remained elevated in the cuneate nucleus (P<0.01) but decreased in the hypoglossal and DMNV (P<0.05) when compared to controls. Active caspase-3 levels were not changed, whereas TUNEL was increased in the DMNV, LRt, and inferior olivary nucleus (P<0.05 for all). These results show that IHH induces neuronal cell death within certain nuclei in the piglet caudal medulla that are functionally important in cardiorespiratory, sleep and arousal control. This could have important implications for clinical conditions including obstructive apnea and prone sleeping as a risk for SIDS.