Abstract: With remote sensing images from 1985, 2000 Lantsat 5 TM and 2015 Lantsat 8 OLI as data sources, we tried to select the suitable research scale and examine the temporal-spatial diffe-rentiation with such scale in the Nansihu Lake wetland by using landscape pattern vulnerability index constructed by sensitivity index and adaptability index, and combined with space statistics such as semivariogram and spatial autocorrelation. The results showed that 1 km × 1 km equidistant grid was the suitable research scale, which could eliminate the influence of spatial heterogeneity induced by random factors. From 1985 to 2015, the landscape pattern vulnerability in the Nansihu Lake wetland deteriorated gradually. The high-risk area of landscape pattern vulnerability dramatically expanded with time. The spatial heterogeneity of landscape pattern vulnerability increased, and the influence of non-structural factors on landscape pattern vulnerability strengthened. Spatial variability affected by spatial autocorrelation slightly weakened. Landscape pattern vulnerability had strong general spatial positive correlation, with the significant form of spatial agglomeration. The positive spatial autocorrelation continued to increase and the phenomenon of spatial concentration was more and more obvious over time. The local autocorrelation mainly based on high-high accumulation zone and low-low accumulation zone had stronger spatial autocorrelation among neighboring space units. The high-high accumulation areas showed the strongest level of significance, and the significant level of low-low accumulation zone increased with time. Natural factors, such as temperature and precipitation, affected water-level and landscape distribution, and thus changed the landscape patterns vulnerability of Nansihu Lake wetland. The dominant driver for the deterioration of landscape patterns vulnerability was human activities, including social economy activity and policy system.