In 13 isolated, perfused guinea pig hearts we determined the coronary flow responses to abrupt elevation of perfusate potassium levels (final concentration 12–16 m M) in the absence and presence of adenosine, and during hypoxic perfusion. Control diastolic coronary flow and spontaneous heart rate averaged 7.85 ± 0.26 ml/min/g and 249.6 ± 2.4 beats/min, respectively. Potassium infusion (12–16 m M) in the absence of other intervention did not alter coronary flow significantly. Repeat potassium elevation in the presence of 0.05 and 0.1 µ M adenosine (threshold dilating doses) produced respective flow increases of 58 and 43% above normokalemic flow (p < 0.05). Paradoxically, during hypoxic perfusion (70%, O<sub>2</sub> or 45 % O<sub>2</sub> in the gas phase) potassium did not elevate flow and, in some instances, constricted the vessels. Myocardial oxygen consumption and effluent potassium levels did not change with adenosine or hypoxic perfusion. These results suggest two points: (1) an interaction between potassium ion and adenosine may be important in the regulation of coronary flow and (2) hypoxic dilation in the coronary vasculature may act via a mechanism different from that of adenosine.