Paleoelevation reconstructions of the North American Cordillera in- ferred from the oxygen (delta 18O) and hydrogen (delta D) isotope ratios of terrestrial paleoclimate proxy materials (soils, ashes, lake sediments) suggest rapid north-to- south migration of topography in the early Cenozoic (pre-49 Ma to 28 Ma). The validation of this reconstruction relies on an accurate understanding of the delta 18Op and the associated regional climate change in response to the uplift of the western North America. Here we study this response using a global climate model (GCM) with explicit delta 18Op diagnostics (ECHAM5-wiso) focusing on the isotopic effects of different types of precipitation, vapor mixing, recycling and moisture source and compare the response against estimates made using a Rayleigh distillation models of moist adiabatic condensation (RDM). Four experiments are performed with Eocene topography inferred from terrestrial stable isotope paleoaltimetry records to investigate how southward propagation of topography affects regional climate (temperature, precipitation and circulation pattern) and dela 18Op over North America. Our experiments predict delta 18Op patterns that are broadly consistent with maps of temporally binned proxy delta 18O and generally support an early Cenozoic north-to-south propagation of high topogra- phy in the North American Cordillera. They do not support the commonly made assumption that isotopic fractionation occurs primarily through rainout following Rayleigh distillation nor the application of modern empirical delta 18Op lapse rates to past environments. In our GCM simulations, precipitation processes and climate changes that are not captured by RDMs substantially affect delta 18Op. These processes include shifts in local precipitation type between convective and large-scale rain and between rain and snow; intensification of low-level vapor recycling particularly on leeward slopes; develop- ment of air mass mixing and changes in wind direction and moisture source. Each of these processes can have significant (>2‰) influences on delta 18Op that are comparable in magnitude to surface uplift of hundreds or even thousands of meters. In many regions, these processes fortuitously compensate each other, explaining the apparent agreement between ECHAM5-wiso and proxy delta 18O and, more broadly, between RDM estimates and observed delta 18O-elevation relationships. In some regions, compensation is incomplete, and as a result, ECHAM5-wiso delta 18Op does not agree with estimates from the RDM. In these regions, including the interior of the northern cordillera and the eastern flank of the southern Cordillera, moderate adjustments of paleoelevations may be in order.