United States and Canadian governments have responded to legal requirements to reduce human-induced whale mortality via vessel strikes and entanglement in fishing gear by implementing a suite of regulatory actions. We analyzed the spatial and temporal patterns of mortality of large whales in the Northwest Atlantic (23.5°N to 48.0°N), 1970 through 2009, in the context of management changes. We used a multinomial logistic model fitted by maximum likelihood to detect trends in cause-specific mortalities with time. We compared the number of human-caused mortalities with U.S. federally established levels of potential biological removal (i.e., species-specific sustainable human-caused mortality). From 1970 through 2009, 1762 mortalities (all known) and serious injuries (likely fatal) involved 8 species of large whales. We determined cause of death for 43% of all mortalities; of those, 67% (502) resulted from human interactions. Entanglement in fishing gear was the primary cause of death across all species (n = 323), followed by natural causes (n = 248) and vessel strikes (n = 171). Established sustainable levels of mortality were consistently exceeded in 2 species by up to 650%. Probabilities of entanglement and vessel-strike mortality increased significantly from 1990 through 2009. There was no significant change in the local intensity of all or vessel-strike mortalities before and after 2003, the year after which numerous mitigation efforts were enacted. So far, regulatory efforts have not reduced the lethal effects of human activities to large whales on a population-range basis, although we do not exclude the possibility of success of targeted measures for specific local habitats that were not within the resolution of our analyses. It is unclear how shortfalls in management design or compliance relate to our findings. Analyses such as the one we conducted are crucial in critically evaluating wildlife-management decisions. The results of these analyses can provide managers with direction for modifying regulated measures and can be applied globally to mortality-driven conservation issues.