The multi-pulse laser treatment of port-wine stains (PWS) has gained much attention owing to its considerable effect on deep and large PWS vessels and the less damage to the epidermis. To reveal the mechanism of the thermal damage to the vessels caused by the multi-pulse Nd:YAG laser, an integrated numerical model of the multi-pulse laser treatment of PWS was developed by combining the voxelbased Monte Carlo (VMC) method for light propagation calculation, the particle form of Pennes bioheat transfer model for heat transfer calculation, and the non-Newtonian moving particle semi-implicit (MPS) method for blood flow and coagulation. An in vitro experimental platform was constructed to visualize coagulation caused by multi-pulse Nd:YAG laser irradiation of the blood in a capillary tube. Numerical results of coagulation shape and area agreed well with experimental results, confirming the validity of the proposed model. Using this integrated model, the thermal damage mechanism of the multi-pulse Nd:YAG laser treatment of PWS was revealed: When a blood vessel is completely obstructed by coagulation, the blood flow is stopped, and subsequent laser pulses always irradiate the same coagulated area and the absorption of laser energy is increased; as a result, the thermal effects of subsequent laser pulses improve remarkably. Finally, the applicable range of the multi-pulse Nd:YAG laser and optimal laser parameters, including frequency, fluence, and pulse number, for clinical practice are recommended. (C) 2017 Elsevier Ltd. All rights reserved.