Shigella flexneri is the major cause of shigellosis in developing countries. A new S. flexneri serotype Xv appeared in 2000 and replaced serotype 2a as the most prevalent serotype in China. Serotype Xv is a variant of serotype X with phosphoethanolamine (PEtN) modification of its O-antigen mediated by a plasmid encoded gene, opt. Serotype Xv isolates belong to sequence type 91 (ST91). In this study, we used Illumina next generation sequencing to elucidate the genomic basis of the epidemic spread of S. flexneri serotype Xv and endemicity of shigellosis in China. A total of 59 S. flexneri isolates including representatives of 14 serotypes (1 to 4, Y, Yv, X and Xv) from different regions of China covering 10 years from 1997 to 2006 were selected for sequencing. The genomes were sequenced using Illumina 100 bp paired-end sequencing with an average of 121 fold coverage. Reads were mapped to the reference sequence 2002017 to produce 4.48 Mb per genome on average. Five published complete S. flexneri genomes were included for comparison. Whole genome sequencing of the 59 S. flexneri isolates indicated that ST91 arose around 1993 by acquiring multidrug resistance (MDR) and spread across China within a decade. Comparative analysis of chromosome and opt-carrying plasmid pSFXv_2 revealed independent origins of 3 serotype Xv clusters in China, with different divergence times. Using 18 cluster-dividing single-nucleotide polymorphism (SNPs), SNP typing divided 380 isolates from three provinces, Henan, Gansu and Anhui, into five SNP genotypes (SGs). Each province was predominated by one SG but substantial inter-region spread of SGs was also evident. These findings suggest that MDR is the key selective pressure for the emergence of the S. flexneri epidemic clone and Shigella epidemics in China was caused by a composite of local expansion and inter-region spread of serotype Xv.