AIMS: Both coronary artery calcification (CAC) and aortic valve calcification (AVC) are strongly associated with cardiovascular diseases (CVDs), but data about the prognostic significance of multiple cardiovascular calcifications are limited. We aim to investigate the interaction relationship between AVC and CAC for major events. METHODS AND RESULTS: We included 6695 participants from the Multi-Ethnic Study of Atherosclerosis at baseline and divided them into four groups: (i) no AVC or CAC; (ii) only AVC; (iii) only CAC; and (iv) with CAC and CAC. The Cox regression model and the Kaplan-Meier method were used to analyse CVD outcomes. We evaluated the interaction between AVC and CAC and their added predictive value based on the pooled cohort equations (PCEs). Subgroup analyses were also explored. Among 6695 participants (mean age 62.2 ± 10.2 years, 47.2% male), after follow-up, 943 cases (14.1%) of CVD and 1274 cases (19.0%) of all-cause death occurred. For participants with both AVC and CAC, the risk of CVD significantly increased [hazard ratio = 3.43 (2.69-4.37), P < 0.001], even higher than the sum of the ones with only AVC and only CAC. This trend remained the same for all-cause death and among subgroup analyses. The addictive interaction was statistically significant (P < 0.001). When AVC and CAC were added, the predictive value of PCEs increased. CONCLUSION: Our results indicated a synergistic interaction between valve calcification and coronary calcification in CVDs. Management for both AVC and CAC may bring health co-benefits in preventing poor outcomes.