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The Andean degu, Octodontomys gliroides Gervais & d’Orbigny, 1844, has a broad distribution inhabiting pre-Andean pre-Puna and Puna environments of tropical South America. In order to understand the phylogeographic patterns of Octodontomys gliroides, we sequenced 579bp of the mitochondrial DNA control region from 100 individuals collected from 20 populations across its entire distributional range. The phylogenetic and parsimony network, in conjunction with analysis of molecular variance (AMOVA), revealed a structured pattern of geographic differentiation of O.gliroides, with the occurrence of two well-defined evolutionary lineages: lineageA, restricted to Bolivia and Chile, and lineageB, restricted mainly to Argentina. Analysis of population structure inferred three genetic clusters along the distribution of O.gliroides that mostly agree with the four major barriers inferred by BARRIER analysis (e.g. rivers, salt flats, deserts, and mountain systems). In addition to the significant differentiation found among all levels studied, a positive correlation was identified between genetic and geographic distance, similar to as expected under the isolation-by-distance model. The most recent common ancestor of O.gliroides was estimated as c.5.99Mya, and the divergence between lineagesA and B is estimated to have occurred by the Middle Pleistocene, about 0.69Mya. The mismatch distributions and neutrality tests suggested a signal of population range expansion for both lineages coincident with major climatic changes that occurred during the wet-dry events of the Pleistocene in the Andean Puna region. Bayesian skyline plots (BSPs) for lineageA suggest a long history of constant population size followed by a period of slight to moderate demographic expansion at c.0.04Mya, whereas lineageB remained unclear after BSP analysis, probably because of the limited sample size.