Lake-water isotopes can be used to track moisture regimes and water sources at present and in the geologic record. However, the effects of seasonal drought and the seasonal distribution of precipitation on lake-water isotopes are not well documented. To improve our understanding of lake-water isotopes, we analyzed the δD and δ18O values of water from a hundred lakes in the western United States across a broad range of seasonal precipitation regimes. Our results show that the isotopic composition of lake-water inputs is correlated with the isotopic composition of annual precipitation. In areas associated with the summer monsoon in northern New Mexico and southern Colorado, lake-water inputs are skewed toward summer precipitation. These results contrast with published western U.S. river-water isotopic data, which are biased toward winter precipitation, and the paradigm that lakes represent the annual moisture surplus. From the lake-water input compositions, on plots of oxygen versus hydrogen isotopes, evaporative enrichment of individual lakes follows regionally coherent evaporation trends (0.96 < r2 < 0.99). We found that the extent of evaporative enrichment in lakes is controlled by local hydrology and is not directly tied to climate or elevation. Our results suggest that paleoclimate reconstructions based on single isotope records could therefore be confounded by multiple factors (i.e., changes in air mass, seasonality of precipitation, temperature, or evaporation). A spatial network of lake-isotope records, however, could be used to separately assess the influences of these multiple factors.