Designing effective local management for invasive species poses a major challenge for conservation, yet factors affecting intervention success and efficiency are rarely evaluated and incorporated into practice. As part of a multi-year study with funding from NOAA Coral Reef Conservation Program and others, REEF and partners coordinated regional efforts by divers to cull invasive lionfish (Pterois spp.) on 33 U.S. Atlantic, Gulf of Mexico, and Caribbean protected coral reefs from 2013 to 2019. During each effort, the researchers estimated removal efficiency and efficacy as a function of environmental and habitat conditions, invasion status, and personnel expertise. Highly experienced individuals culling during crepuscular periods (2 hr from sunrise/sunset) are three times more efficient (in terms of minutes) than novice divers during midday, suggesting: (a) retention of experienced individuals is key for efficient programs, and (b) planning culls with personnel and time of day in mind increases the number of sites covered with the same effort. Lionfish behavior and habitat characteristics had little effect on removal efficiency and efficacy, but divers had higher capture success at reefs with higher lionfish densities. The authors suggest reefs with persistently low densities of lionfish be given low priority for management efforts, given that impacts to native fauna are unlikely and culling effectiveness declines to <50% below this level. Incorporating efficiency factors in spatial management planning along with estimates of lionfish density can help ensure that limited resources for control are extended across a greater range of invaded habitats.