As the IC feature size continues to decrease, interconnect cross-talk noise with the process fluctuation is also a corresponding increase in sensitivity. The impact of interconnect process fluctuation on the interconnect cross-talk noise in Very Large Scale Integration(VLSI) was studied and discussed in this study. The approximate function relationships were obtained by analyzing the impact of interconnect geometric parameters fluctuation on the interconnect parasitic parameters. On the basis of these studies, the statistical cross-talk noise model was successfully proposed and built. The expressions of mean and standard deviation of interconnect cross-talk noise could be obtained from this model. Compared with HSPICE, the computation results showed that the time of calculation was greatly shortened with a good calculating precision using the proposed method. It will have a potential bright future in the analysis and optimization of VLSI interconnects signal integrity.