Periodic breathing (PB) is an instability of the respiratory control system believed to be mediated principally by the peripheral chemoreceptors. We hypothesised that domperidone, a dopamine D(2)-receptor antagonist that increases carotid body sensitivity to O(2) and CO(2), would promote PB through an increase in the loop gain (LG) of the respiratory control system. Domperidone significantly increased controller gain for oxygen (p<0.05) and gave rise, following post-hyperventilation apnea, to an increased incidence of PB (14% vs. 86%), an increased PB epoch duration, and a decrease in duty ratio of PB (p<0.001); these changes are consistent with domperidone increasing LG. Although domperidone increased controller gain for CO(2) (p<0.05), the contribution of Pa(CO)(2) oscillations to the genesis of PB in the lamb remained small. We conclude that domperidone increases LG in the lamb via an increase in controller gain for oxygen. Our study demonstrates that a quantitative understanding of the factors that determine LG provides insight into the cause of PB.