The stable oxygen isotopic composition of precipitation (δ18Op) is used as a proxy for modern and past atmospheric, biologic, and surface processes. Although the physical processes that fractionate 18O in vapor are known, regional controls of δ18Op are not well understood. Here we present results from a limited-domain general circulation model (REMOiso) to quantify regional controls on modern (1976–1999) interannual and spatial variations of δ18Op across four Andean domains spanning 50° latitude. Results are compared to observed δ18Op from meteorological stations. Simulated annual amount-weighted mean δ18Op ranges between −4 and −7‰ (0–5°S), −8 and −20‰ (14°S–26°S), −4 and −8.5‰ (30°S–35°S), and −7 to −10‰ (45°S–50°S). Relationships between climate and δ18Op on interannual timescale vary along the Andes and are tied to changes in precipitation and large-scale dynamics. In the northern Andes, interannual variations in δ18Op are mainly associated with precipitation amounts driven by low-latitude sea surface temperature and Amazon Basin conditions. In the north central Andes, δ18Op correlates with precipitation amount and wind trajectory, which is related to the position of the Bolivian High. In the south central Andes, δ18Op variability is mainly influenced by precipitation amounts that are controlled by the position and strength of the westerlies. In the southern Andes, interannual δ18Op variability is linked to the intensification and weakening of the South Pacific High. The regional climate-δ18Op relationships are discussed in the context of pre-Quaternary sedimentary δ18O proxy records.