The Sangre de Cristo Range in southern Colorado exposes some of the deepest Cenozoic structural levels in the Rocky Mountain region, including mylonitic shear zones associated with both the Laramide orogeny and Rio Grande rift. We investigated the relation between Laramide contraction and Rio Grande rift extension with detailed geologic mapping, kinematic analysis, and geochronometry in a 50 km² area centered on the Independence Mine shear zone (IMSZ). The 15−100-m-thick IMSZ is one of several shallowly to moderately (∼45° ± 20°) W-SW−dipping brittle-plastic shear zones along the western flank of the range. These shear zones display microstructural evidence of initiation as top-NE contractional mylonite zones, consistent with regional Laramide kinematics, which have been pervasively overprinted by shear fabrics indicating top-SW extensional reactivation. Both top-NE and top-SW shear fabrics involve cataclasis and quartz dislocation creep, although top-SW shear is more commonly localized along phyllosilicate-lined shear bands. Shear zones are hosted predominately within Proterozoic gneiss, and contain abundant chlorite and white mica derived from alteration of hornblende and feldspar, which indicates that weakening driven by fluid reactions played an important role in localizing strain. Extensional overprinting appears to be most pervasive along more steeply dipping portions of shear zones and where secondary phyllosilicates form an interconnected weak phase, which suggests that reactivation was primarily controlled by geometry and rheological contrasts inherited from contraction. One top-SW shear zone adjacent to the IMSZ cuts a late Oligocene gabbro stock, and monazite grains synkinematic with top-SW shear in the IMSZ yielded late Oligocene to Early Miocene U-Th-Pb dates that correspond with initiation of the Rio Grande rift. Reactivation of weak reverse faults may represent an important structural control during initial extension in the middle crust, prior to slip along the high-angle Sangre de Cristo normal fault system.