Background Although the effects of fine particulate matter (particulate matter ≤2.5 μm aerodynamic diameter [PM _2.5 ]) on cardiovascular disease (CVD) morbidity and mortality are well established, little is known about the CVD health effects of particle radioactivity. In addition, there are still questions about which of the PM _2.5 physical, chemical, or biological properties are mostly responsible for its toxicity. Methods and Results We investigated the association between particle radioactivity, measured as gross β activity from highly resolved spatiotemporal predictions, and mortality for CVD, myocardial infarction, stroke, and all‐cause nonaccidental mortality in Massachusetts (2001–2015). Within both difference‐in‐differences model and generalized linear mixed model frameworks, we fit both single‐exposure and 2‐exposure models adjusting for PM _2.5 and examined the interaction between PM _2.5 and gross β activity. We found significant associations between gross β activity and PM _2.5 and each mortality cause. Using difference‐in‐differences and adjusting for PM _2.5 , we found the highest associations with myocardial infarction (rate ratio, 1.16 [95% CI, 1.08–1.24]) and stroke (rate ratio, 1.11 [95% CI, 1.04–1.18]) for an interquartile range increase (0.055 millibecquerels per cubic meter) in gross β activity. We found a significant positive interaction between PM _2.5 and gross β activity, with higher associations between PM _2.5 and mortality at a higher level of gross β activity. We also observed that the associations varied across age groups. The results were comparable between the 2 statistical methods also with and without adjusting for PM _2.5 . Conclusions This is the first study that, using highly spatiotemporal predictions of gross β‐activity, provides evidence that particle radioactivity increases CVD mortality and enhances PM _2.5 CVD mortality. Therefore, particle radioactivity can be an important property of PM _2.5 that must be further investigated. Addressing this important question can lead to cost‐effective air‐quality regulations.