Introduction: Cannabis is frequently used and increasingly legalized in the U.S., and 27.7 million Americans aged >= 12 years are currently using cannabis. However, the public health effects of can-nabis use in the general population remain unclear. This study examines the associations of cannabis use with all-cause and cause-specific mortality in U.S. adults. Methods: The study included 14,818 adults (aged 20-59 years) who participated in the National Health and Nutrition Examination Survey from 2005 to 2014 and were free of cardiovascular disease or cancer at baseline. Survey participants were linked to mortality records through December 31, 2015. The outcomes included all-cause mortality, cardiovascular disease mortality, and cancer mortality. All statistical analyses were conducted in 2019. Results: During 86,453 person-years of observation, 304 deaths occurred, including 39 deaths from cardiovascular disease and 79 deaths from cancer. After adjustment for a variety of potential confounders, the hazard ratios for all-cause mortality, cardiovascular disease mortality, and cancer mortality among cannabis ever users, compared with the ratios among nonusers, were 1.14 (95% CI=0.81, 1.59), 2.29 (95% CI=1.10, 4.78), and 0.67 (95% CI=0.40, 1.14), respectively. The hazard ratios for cardiovascular disease mortality among cannabis users, compared with those among nonusers, were 1.65 (95% CI=0.57, 4.89) if the use was first initiated at age >= 18 years and 3.00 (95% CI=1.41, 6.38) if the use was first initiated before age 18 years. Conclusions: Cannabis use was significantly associated with an increased risk of cardiovascular disease mortality among U.S. adults, especially among those who started using cannabis before age 18 years. The reasons and mechanisms underlying this association will require future research. (c) 2020 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.