Large millennial-scale fluctuations of the southern margin of the North American Laurentide Ice Sheet occurred during the last deglaciation, when the margin was located between about 43° and 49°N. Fluctuations of the ice margin triggered episodic increases in the flux of freshwater to the North Atlantic by rerouting continental runoff from the Mississippi River drainage to the Hudson or St. Lawrence Rivers. We found that periods of increased freshwater flow to the North Atlantic occurred at the same time as reductions in the formation of North Atlantic Deep Water, thus providing a mechanism for observed climate variability that may be generally characteristic of times of intermediate global ice volume.