We studied cardiac lymph circulation in relation to changes in coronary blood flow (CBF), myocardial contractility, and heart rate (HR) in 17 open-chest dogs. We developed a method of direct cannulation into subepicardial lymph vessels, which allowed us to study regional myocardial lymph circulation. Control values for the lymph flow rate (LF) ranged from 5.3 to 10.6 μ 1/ml. Adenosine, serotonin, histamine, and isoproterenol increased LF and protein efflux in cardiac lymph (PEF), and decreased protein concentrations (PC) concomitantly with coronary blood flow (CBF) increments. The relative increase of LF to CBF change was significantly greater upon administration of histamine and isoproterenol than with adenosine and serotonin. PC in the lymph were decreased by adenosine and serotonin, while no significant changes in PC were seen upon histamine or isoproterenol infusion. These results indicate that increased water release was greater than any protein efflux into cardiac with increased CBF, and that histamine and isoproterenol can modify capillary permeability directly or by changes in myocardial metabolism. An increased heart rate decreases LF and PEF possibly due to shortening of the diastolic time in the heart cycle.