We examined the temporal kinetics of onset and offset of the cardiac electrophysiologic effects of orally administered amiodarone in chronically instrumented, unsedated, adult dogs (n = 8). Right atrial (RA), atrioventricular nodal (AVN), and right ventricular (RV) effective refractory period (ERP), and AVN functional refractory period (FRP), were determined daily for 21 days during amiodarone loading (24 mg/kg/day) and for 21 days after cessation of amiodarone. Left ventricular (LV) ERP was assessed in four of eight animals. Group mean RA-ERP peaked and plateaued early during amiodarone loading (time to reach one-half observed peak change [t 1/2 onset] = 1.2 ± 0.5 days) and rapidly returned toward baseline after cessation of drug (decay time to one-half peak value [t 1/2 offset] = 2.0 ± 1.7 days). Group mean RV-ERP rose in a linear manner throughout the loading period (t 1/2 onset = 9.3 ± 2.1 days) and remained elevated after cessation of drug (t 1/2 offset > 21.0 days). Group mean AVN-ERP and FRP exhibited temporal kinetics intermediate between those of the RA-ERP and RV-ERP, both during amiodarone loading and after cessation of the drug. Group mean LV-ERP onset kinetics (assessed in a limited number of animals, n = 4) appeared to differ from RV-ERP onset kinetics (t 1/2 onset = 2.5 ± 2.5 days), whereas LV-ERP and RV-ERP offset kinetics appeared similar (t 1/2 offset > 21 days). In summary, our findings demonstrate that during oral loading, the temporal sequence of onset of amiodarone-induced electrophysiologic effects is site dependent. Similarly, after cessation of amiodarone, the persistence of drug-induced electrophysiologic effects is both variable and site dependent.