The use of the plasma noradrenaline (NA) concentration as an index of sympathetic nervous system (SNS) activity in the postprandial state is associated with several problems: (i) It does not take into account the contribution of alterations in clearance to the plasma NA level, (ii) when antecubital venous blood is sampled, it reflects regional forearm rather than whole body SNS activity and (iii) no insight is gained into the regional pattern of SNS activation. These potential confounders were addressed in this study performed in 17 healthy young men. The validity of plasma NA measurements in assessing postprandial changes in sympathetic nervous activation was evaluated in relation to that of whole body and regional plasma NA spillover, derived using isotope dilution methodology. Plasma clearance of NA is significantly altered following a meal, with a transient elevation in the early postprandial phase which may lead to an underestimation of SNS activation when assessed from arterial plasma NA levels. Forearm plasma NA spillover increases postprandially, such that despite significant postprandial elevations in arterial plasma NA, the plasma arterial contribution to antecubital venous plasma NA levels is maintained at less than 40%, the rest being derived locally from the forearm. This makes venous plasma samples unsuitable for the assessment of SNS activation in organs and vascular sites distant from the sampling site. The kidneys and skeletal muscle are the major regional sites of postprandial sympathetic nervous activation, while cardiac plasma NE spillover is unaltered postprandially. This regional pattern of SNS activation postprandially must be taken into account when relating increments in plasma NA levels to specific physiological events.