Abstract: To elucidate the molecular mechanisms underlying the resistance and susceptibility of larch to larch shoot blight, as well as to uncover the driving factors behind this disease, the responsible pathogen was identified through comprehensive morphological and phylogenetic analyses. The resistance and susceptibility of larch were further evaluated via artificial inoculation. Moreover, multi-omics analyses were employed to elucidate the mechanisms of resistance and susceptibility. The findings revealed that: 1） Neofusicoccum laricinum （Sawada） Hattori & C. Nakash. was identified as the causal agent of larch shoot blight, effectively distinguishing it from other pathogens responsible for shoot blight. 2） Artificial inoculation demonstrated varying levels of resistance among different larch families to N. laricinum. Larches susceptible to the pathogen exhibited consistently elevated reactive oxygen species （ROS） signaling, leading to a rapid onset of new shoot blight. Conversely, resistant larches displayed only mild ROS signaling during the initial stages of infection. 3） Multi-omics analyses have demonstrated that resistant larches accumulated 6 phytoalexins, including quinic acid and vanillin, via the shikimate-phenylpropanoid metabolic pathway, thereby inhibiting pathogen growth. In contrast, susceptible larches exhibited excessive ROS production and failed to synthesize sufficient phytoalexins, which facilitated disease progression. Furthermore, field monitoring and artificial inoculation showed that the widespread distribution of susceptible larches significantly contributed to larch shoot blight outbreaks. The results revealed that the wide distribution of susceptible individuals led to the vulnerability of larch population, which was the driving factor of larch withering disease. Underscoring the importance of investigating host resistance resources as a comprehensive strategy for managing invasive fungal pathogens.