Position time series from Global Positioning System (GPS) stations in the New Madrid region were differenced to determine the relative motions between stations. Uncertainties in rates were estimated using a three‐component noise model consisting of white, flicker, and random walk noise, following the methodology of Langbein, 2004. Significant motions of 0.37±0.07 (one standard error) mm/yr were found between sites PTGV and STLE, for which the baseline crosses the inferred deep portion of the Reelfoot fault. Baselines between STLE and three other sites also show significant motion. Site MCTY (adjacent to STLE) also exhibits significant motion with respect to PTGV. These motions are consistent with a model of interseismic slip of about 4 mm/yr on the Reelfoot fault at depths between 12 and 20 km. If constant over time, this rate of slip produces sufficient slip for an M 7.3 earthquake on the shallow portion of the Reelfoot fault, using the geologically derived recurrence time of 500 years. This model assumes that the shallow portion of the fault has been previously loaded by the intraplate stress. A GPS site near Little Rock, Arkansas, shows significant southward motion of 0.3–0.4 mm/yr (±0.08 mm/yr) relative to three sites to the north, indicating strain consistent with focal mechanisms of earthquake swarms in northern Arkansas.