Background: All fifty U.S. states and the District of Columbia implemented social distancing measures that interrupted transmission TRANS of severe acute respiratory syndrome MESHD coronavirus 2 (SARS-CoV-2) and reduced morbidity and mortality from coronavirus disease MESHD 2019 (COVID-19). All 51 jurisdictions have since begun to relax these measures, albeit in an uncoordinated fashion. Methods: We obtained state-level data on implementation and relaxation of social distancing measures. We fitted mixed-effects linear regression models with a random effect for state, specifying the time-varying, state-specific effective reproduction number TRANS (Rt, the expected number of secondary infections TRANS infections MESHD generated by each index case given date-specific population susceptibility and risk behavior). Explanatory variables included time in days, implementation period (1-21 days prior to first relaxation of any statewide social distancing measure vs. time from relaxation through May 28, 2020), and a time-by-period product term. Results: During the three weeks prior to relaxation, the estimated Rt was declining by an average of 0.0016 units per day (95% confidence interval [CI], -0.0025 to -0.0008). At the time of initial relaxation, states had reported a median 7,628 cases (range, 337-361,313) and 289 COVID-attributable deaths MESHD (range, 7-28,663), and the median estimated Rt was 1.0 (range, 0.8-1.3) (i.e., the median rate of epidemic growth across states was estimated to be zero). After the first relaxation of statewide social distancing measures, the estimated Rt began increasing by an average of 0.0047 units per day (95% CI, 0.0037 to 0.0058) compared with the pre-relaxation period. If these trends continue, the estimated state-level Rt would reach an average value of 1.05 (95% CI, 1.03-1.07) by 30 days after relaxation and 1.15 (95% CI, 1.11-1.18) by 60 days. A similar upward trajectory in the estimated Rt was observed after relaxation of statewide restrictions on internal movement. Conclusions: Relaxation of U.S. statewide social distancing measures was associated with a subsequent reversal of an earlier downward trend in transmission TRANS of SARS-CoV-2, particularly in states with less active epidemics at the time of relaxation.