The aim of this study was to investigate the impact of changes in local blood flow on the recovery of a small, diffusible molecule (sodium fluorescein) from the extravascular tissue space of the skin, by microdialysis in vivo. Loss and recovery of fluorescein by linear microdialysis probes (5-kDa molecular mass cutoff, 0.2 mm diameter) inserted 1 mm apart in pairs, at three sites in the skin of the volar surface of the forearm of healthy volunteers, was measured under conditions of basal, reduced (noradrenaline, 0.005 mg/ml), and increased (glyceryl trinitrate, patch) blood flow. Whereas loss of tracer from the delivery probe appeared unaffected by changes in local blood flow, retrieval of fluorescein by the second probe was directly related to blood flux, measured using scanning laser Doppler imaging. Steady-state recovery at vasoconstricted sites was 4.0 Ϯ 0.7 g ⅐ ml Ϫ1 compared with 1.8 Ϯ 0.7 g ⅐ ml Ϫ1 at control sites (p Ͻ 0.001). Local vasodilatation reduced the retrieval of fluorescein by ϳ50% to give a steadystate concentration of fluorescein in the dialysate at 40 to 50 min after the start of perfusion of 0.9 Ϯ 0.3 g ⅐ ml Ϫ1 (p ϭ 0.05). These studies in the skin are consistent with microdialysis theory. They suggest that clearance of solute by the blood will have a significant impact on microdialysis probe recovery and that, in the skin, the magnitude of this clearance is directly related to blood flow.Microdialysis is a well established technique for continuous sampling of small, water-soluble molecules within the extracellular fluid space in vivo. It was used initially for the recovery of neurotransmitters from the brains of experimental animals (Bito et al., 1966). Since then it has been adapted for use in many other tissues including skin (Petersen et al