Background: Vascular targeted photodynamic therapy (V-PDT) is a safe and effective therapeutic modality for port-wine stains (PWS) by targetedly damaging the dilated and malformed blood vessels. This study aims to monitor and quantify the changes in oxygen saturation (StO 2 ), blood volume fraction (BVF) and perfusion in PWS lesions before and during V-PDT. Methods: Microvascular parameters (i.e., StO 2 and BVF) and skin perfusion were measured noninvasively by using diffuse reflectance spectroscopy (DRS) and laser Doppler imaging (LDI), respectively. The change in StO 2 , BVF and perfusion that occurred in the PWS lesions of 26 patients were monitored and investigated before and during V-PDT in vivo with the systematic administration of the porphyrin-based photosensitizer HiPorfin.Results: The mean StO 2 (P<0.05), BVF (P<0.05), and perfusion (P<0.001) in PWS lesions of all subjects significantly increased by 6%, 34%, and 113%, respectively, 3 min after the initiation of V-PDT. The StO 2 increased first and fluctuated during V-PDT. The overall trend of BVF change was consistent with the perfusion change. The BVF and the perfusion of PWS lesions increased after the initiation of V-PDT, and then gradually decreased.Conclusions: V-PDT is an effective therapeutic modality in treating PWS. Results showed that LDI and DRS permitted the noninvasive monitoring of the changes in StO 2 , BVF, and perfusion in PWS lesions during V-PDT, and these methods can be useful in facilitating our understanding of the basic physiological mechanisms during V-PDT.