Collisions with vessels are a serious threat to a number of endangered large whale species, the North Atlantic right whale (Eubalaena glacialis) in particular. In late 2008, the U.S. National Oceanic and Atmospheric Administration issued mandatory time-area vessel speed restrictions along the U.S. eastern seaboard in an effort to mediate collision-related mortality of right whales. All vessels 65 feet and greater in length are restricted to speeds of 10 knots or less during seasonally implemented regulatory periods. We modeled mortality risk of North Atlantic right whale when the vessel restrictions were and were not in effect, including (1) estimation of the probability of lethal injury given a ship strike as a function of vessel speed, (2) estimation of the effect of transit speed on the instantaneous rate of ship strikes, and (3) a consideration of total risk reduction. Logistic regression and Bayesian probit analyses indicated a significant positive relationship between ship speed and the probability of a lethal injury. We found that speeds of vessels that struck whales were consistently greater than typical vessel speeds for each vessel type and regulatory period studied; a use-availability model fit to these data provided strong evidence for a linear effect of transit speed on strike rates. Overall, we estimated that vessel speed restrictions reduced total ship strike mortality risk levels by 80–90% with levels that were closer to 90% in the latter two of the four active vessel speed restriction periods studied. To our knowledge, this is the most comprehensive assessment to date of the utility of vessel speed restrictions in reducing the threat of vessel collisions to large whales. Our findings indicate that vessel speed limits are a powerful tool for reducing anthropogenic mortality risk for North Atlantic right whales.