An unprecedented increase in earthquakes in the U.S. mid-continent began in 2009. Many of these earthquakes have been documented as induced by wastewater injection. We examine the relationship between wastewater injection and U.S. mid-continent seismicity using a newly assembled injection well database for the central and eastern United States. We find that the entire increase in earthquake rate is associated with fluid injection wells. High-rate injection wells (>300,000 barrels per month) are much more likely to be associated with earthquakes than lower-rate wells. At the scale of our study, a well’s cumulative injected volume, monthly wellhead pressure, depth, and proximity to crystalline basement do not strongly correlate with earthquake association. Managing injection rates may be a useful tool to minimize the likelihood of induced earthquakes.