Abstract: The Yarlung Zangbo River (the upper Brahmaputa River) is the largest river on the Tibetan Plateau. The present study investigated the genetic diversity and population demography of Schizothorax molesworthi from the Motuo area of lower reaches of the Yarlung Zangbo River and Lohit River using mitochondrial DNA Cyt b gene sequences. The results showed that 21 haplotypes were identified for 167 individuals with relatively high haplotype diversity (h= 0.768) and low nucleotide diversity (π=0.00167). Phylogenetic trees and Network diagram based on haplotypes indicated all haplotypes from the lower reaches of the Yarlung Zangbo River and Lohit River were not clustered separately but mixed with each other according to the geographical distribution. Pairwise comparisons of genetic diffe-rentiation index (F_ST) among different populations ranged from –0.014 to 0.771 with highly significant genetic differentiations between the JZZB population and other populations (F_ST: 0.372—0.771). The analysis of molecular variance (AMOVA) showed that the largest mean F_CT index was found between JZZB population and the group of other six populations. Neutral test, mismatch analysis and BSP (Bayesian skyline plot) analysis showed that overall S. molesworthi population from the lower reaches of the Yarlung Zangbo River and Lohit River experienced population expansion during the last glaciations BP (0—0.137 Ma).