Field mapping and geochronologic and thermobarometric analyses of the Gurla Mandhata area, in southwest Tibet, reveal major middle to late Miocene, east-west extension along a normal-fault system, termed the Gurla Mandhata detachment system. The maximum fault slip occurs along a pair of low-angle normal faults that have caused significant tectonic denudation of the Tethyan Sedimentary Sequence, resulting in juxtaposition of weakly metamorphosed Paleozoic rocks and Tertiary sedimentary rocks in the hanging wall over amphibolite-facies mylonitic schist, marble, gneisses, and variably deformed leucogranite bodies in the footwall. The footwall of the detachment fault system records a late Miocene intrusive event, in part contemporaneous with top-to-the-west ductile normal shearing. The consistency of the mean shear direction within the mylonitic footwall rocks and its correlation with structurally higher brittle normal faults suggest that they represent an evolving low-angle normal-fault system. 40Ar/39Ar data from muscovite and biotite from the footwall rocks indicate that it cooled below 400 °C by ca. 9 Ma. Consideration of the original depth and dip angle of the detachment fault prior to exhumation of the footwall yields total slip estimates between 66 and 35 km across the Gurla Mandhata detachment system. The slip estimates and timing constraints on the Gurla Mandhata detachment system are comparable to those estimated on the right-slip Karakoram fault system, to which it is interpreted to be kinematically linked. Moreover, the mean shear-sense direction on both the Karakoram fault and the Gurla Mandhata detachment system overlap along the intersection line between the mean orientations of the faults, which further supports a kinematic association. If valid, this interpretation extends previous results that the Karakoram fault extends to mid-crustal depths.