An isotope-enabled ocean-atmosphere general circulation model (GISS ModelE-R) is used to estimate the spatial gradients of the oxygen isotopic composition of seawater (δ18Osw, where δ is the deviation from a known reference material in per mil) during the early Paleogene (45–65 Ma). Understanding the response of δ18Osw to changes in climatic and tectonic boundary conditions is important because records of carbonate δ18O document changes in hydrology, as well as changes in temperature and global ice-volume. We present results from an early Paleogene configuration of ModelE-R which indicate that spatial gradients of surface ocean δ18Osw during this period could have been significantly different to those in the modern ocean. The differences inferred from ModelE-R are sufficient to change early Paleogene sea surface temperature estimates derived from primary carbonate δ18O signatures by more than ±2°C in large areas of the ocean. In the North Atlantic, Indian, and Southern Oceans, the differences in δ18Osw inferred from our simulation with ModelE-R are in direct contrast with those from another δ18O-tracing model study which used different, but equally plausible, early Paleogene boundary conditions. The large differences in δ18Osw between preindustrial and early Paleogene simulations, and between models, emphasizes the sensitivity of δ18Osw to climatic and tectonic boundary conditions. For this reason, absolute estimates of Eocene/Paleocene temperature derived from carbonate δ18O alone are likely to have larger uncertainties than are usually assumed.