On the basis of combined mechanical modeling and isotopic observations, we propose a Southern Alps paradigm for application to fluid-flow regimes of active oblique collision zones subject to orographic precipitation. The model is derived from four spatial correlations among patterns in the distribution of mechanical forces that drive fluid flow, structural permeability, and isotopic signature. (1) A strong meteoric overprint of a deep isotopic signature in the inboard adjacent to the plate boundary is associated with oblique reverse faulting. In these rocks, exhumed rapidly from depth, the isotopic signature is dominated by rock advection and limited vertical movement of fluids. (2) The region along the main divide characterized by net expansion, rotation, and steep failure planes is associated with an isotopic signature of anomalously deep fluids in shallow rocks. (3) A high-strain zone within the root of the deforming orogen produces fluids during strain-induced metamorphism. (4) Basinal and meteoric fluids interact at shallow levels in the outboard region, which undergoes net contraction and rotation in an oblique thrust belt. We suggest that these four correlations represent a predictable pattern that is characteristic of all oblique orographic orogens. Rock advection is the dominant process influencing the isotopic signature adjacent to the plate boundary, where strain and erosion rates are high. Water advection exerts the dominant influence on isotopic signature in the region of net expansion near the main divide, where steep structures tap the source of deep fluids in the underlying high-strain detachment and crustal root.