Systemic vascular resistance (SVR) is a frequently used clinical index of left ventricular afterload. However, SVR may not adequately assess left ventricular afterload (i.e., ventricular internal fiber load during systole) since it reflects only peripheral vasomotor tone. In contrast, left ventricular end-systolic wall stress (ces) reflects the combined effects of peripheral loading conditions and left ventricular chamber pressure, dimension, and wall thickness. To determine the relationship between SVR and cyes, left ventricular afterload and contractility were pharmacologically altered in eight dogs instrumented with central aortic microtip and Swan-Ganz thermodilution catheters. Left ventricular wall thicknesses and dimensions were measured from two-dimensionally targeted M mode echocardiograms. Aortic, right atrial, and left ventricular end-systolic pressures as well as cardiac output were recorded. SVR and aes were determined under control conditions as well as during infusions of nitroprusside, methoxamine, dobutamine, and norepinephrine. Control data acquired before each drug infusion were similar. When compared with baseline values, SVR underestimated the magnitude of change in left ventricular Cyes by (1) 22% when afterload alone was decreased (nitroprusside), (2) 54% when afterload alone was increased (methoxamine), and (3) 50% when afterload was decreased and contractility was augmented (dobutamine). Most importantly, when afterload was minimally decreased in association with augmented contractility (norepinephrine), SVR increased by 21% while, es fell by 9%. Thus, discordant changes in left ventricular afterload (i.e., a,) and SVR can occur during pharmacologic interventions. SVR is an unreliable index of left ventricular afterload, reflecting only peripheral arteriolar tone rather than left ventricular systolic wall force. This emphasizes the fact that a true measure of left ventricular afterload must consider the interaction of factors internal and external to the myocardium.