Importance It is unclear whether, for the same amount of total physical activity, a higher proportion of vigorous physical activity (VPA) to total physical activity is associated with a greater reduction in mortality. Objective To examine the association of the proportion of VPA to total physical activity (defined as moderate to vigorous physical activity [MVPA]) with all-cause mortality, cardiovascular disease mortality, and cancer mortality. Design, Setting, and Participants This cohort study included 403 681 adults from the National Health Interview Survey 1997-2013 who provided data on self-reported physical activity and were linked to the National Death Index records through December 31, 2015. Statistical analysis was performed from May 15, 2018, to August 15, 2020. Exposures Proportion of VPA to total physical activity among participants performing any MVPA. Main Outcomes and Measures All-cause mortality, cardiovascular disease mortality, and cancer mortality. Cox proportional hazards regression models were performed to estimate hazard ratios (HRs) and 95% CIs, adjusted for sociodemographic characteristics, lifestyle risk factors, and total physical activity. Result Among the 403 681 individuals (225 569 women [51.7%]; mean [SD] age, 42.8 [16.3] years) in the study, during a median 10.1 years (interquartile range, 5.4-14.6 years) of follow-up (407.3 million person-years), 36 861 deaths occurred. Mutually adjusted models considering the recommendations of moderate physical activity (MPA; 150-299 vs 0 minutes per week) and VPA (>= 75-149 vs 0 minutes per week) showed similar associations for all-cause mortality (MPA: HR, 0.83; 95% CI, 0.80-0.87; and VPA: HR, 0.80; 95% CI, 0.76-0.84) and cardiovascular disease mortality (MPA: HR, 0.75; 95% CI, 0.68-0.83; and VPA: HR, 0.79; 95% CI, 0.70-0.91). For the same contrasts, VPA (HR, 0.89; 95% CI, 0.80-0.99) showed a stronger inverse association with cancer mortality compared with MPA (HR, 0.94; 95% CI, 0.86-1.02). Among participants performing any MVPA, a higher proportion of VPA to total physical activity was associated with lower all-cause mortality but not with cardiovascular disease and cancer mortality. For instance, compared with participants with 0% of VPA (no vigorous activity), participants performing greater than 50% to 75% of VPA to total physical activity had a 17% lower all-cause mortality (hazard ratio, 0.83; 95% CI, 0.78-0.88), independent of total MVPA. The inverse association between proportion of VPA to total physical activity and all-cause mortality was consistent across sociodemographic characteristics, lifestyle risk factors, and chronic conditions at baseline. Conclusions and Relevance This study suggests that, for the same volume of MVPA, a higher proportion of VPA to total physical activity was associated with lower all-cause mortality. Clinicians and public health interventions should recommend 150 minutes or more per week of MVPA but also advise on the potential benefits associated with VPA to maximize population health. Question Is vigorous physical activity associated with additional mortality risk reduction compared with moderate physical activity? Findings In this cohort study of 403 681 participants, a higher proportion of vigorous physical activity to total moderate to vigorous physical activity was associated with statistically significantly lower all-cause mortality. For the same amount of total moderate to vigorous physical activity, participants with a greater proportion of vigorous physical activity to moderate physical activity had lower all-cause mortality. Meaning Although most of the health benefit associated with meeting recommended weekly physical exercise goals may be achieved through moderate physical activity, the results suggest that an increased proportion of vigorous physical activity is associated with additional health benefits. This cohort study uses data from the National Health Interview Survey to examine the association of the proportion of vigorous physical activity to total physical activity with all-cause mortality, cardiovascular disease mortality, and cancer mortality.