Background　and　Objective:　Port　wine　stains　(PWS)　are　congenital　vascular　malformations　that　progressively　darken　and　thicken　with　age.　Laser　therapy　is　currently　the　most　effective　way　in　clinical　practice　for　PWS.　A　1,064　nm　Nd:YAG　laser　in　the　near-infrared　band　can　achieve　a　deeper　treatment　depth　compared　to　the　current　widely　adopted　pulsed　dye　laser.　However,　because　of　its　relatively　weak　absorption　by　blood,　single-pulse　Nd:　YAG　laser　requires　high　energy　density　to　cause　effective　vessel　damage,　but　may　inflict　undesirable　burning　to　surrounding　collagen.　Multi-pulse　laser　has　great　potential　in　clinical　treatment　because　it　needs　less　energy　density　for　each　pulse.　This　paper　presented　an　experimental　and　theoretical　study　of　the　transient　thermal　effects　of　low-energy　multi-pulse　Nd:　YAG　laser　on　blood　vessels.　Study　Design/Materials　and　Methods:　In　vivo　experiments　were　performed　on　dorsal　skin　chamber.　By　using　a　high　speed　camera　(up　to　2,000　fps),　the　complete　and　dynamic　thermal　response　of　blood　vessels　during　laser　irradiation　and　between　pulse　intervals　was　obtained.　In　vitro　experiment　in　capillary　tubes　and　Numerical　simulations　by　two-scale　heat　transfer　model　were　also　conducted　to　further　explore　the　in　vivo　experimental　findings.　Results:　The　complete　and　dynamic　response　of　blood　vessels　were　obtained,　including　vessel　dilation,　thrombus　formation,　partial　vessel　constriction,　thread-like　constriction,　cavitation　and　bubbles,　and　hemorrhage.　Thread-like　constriction　is　the　desirable　treatment　end　point,　which　will　only　occur　after　thrombus　completely　occludes　the　vessel　lumen.　Cavitation　can　cause　hemorrhage　when　thrombus　fails　to　occlude　the　vessel　lumen.　In　vitro　experiment　found　that　vessel　constriction　was　due　to　the　constriction　of　thrombus　induced　by　laser　irradiation.　Theoretical　investigation　revealed　that　the　mechanism　for　the　effective　reduction　of　energy　density　by　multi-pulse　Nd:　YAG　laser　was　due　to　enhanced　light　absorption　of　the　blood　with　thrombus　formation.　Conclusions:　For　multi-pulse　treatment,　laser　parameters　are　recommended　as　repetition　rate　of　10　Hz　and　pulse　number　of　10.　The　incident　energy　in　each　pulse　should　be　strong　enough　to　induce　blood　coagulation　through　seven　or　eight　pulses　and　should　be　lower　than　the　threshold　of　blood　cavitation.　(C)　2017　Wiley　Periodicals,　Inc.