BACKGROUND: While observational studies have indicated a potential link between cancer and coronary atherosclerosis, the relationship remains obscured by confounding factors. Elucidating a shared genetic basis may uncover common pathophysiological pathways. METHODS: We employed a two-sample Mendelian randomization (MR) approach to evaluate causal relationships between 23 cancer types and coronary atherosclerosis. Reverse MR analysis was also conducted to explore potential bidirectional effects. Given the exploratory nature of this pan-cancer analysis, we report nominal significance (p < 0.05) without multiple-testing correction. RESULTS: Forward MR analysis identified nominally significant associations between coronary atherosclerosis and five cancer types; however, after rigorous sensitivity analyses, only the inverse associations with pancreatic cancer (OR = 0.90, 95%CI = 0.83-0.98 and hepatic cancer (OR = 0.87, 95%CI = 0.81-0.94 remained robust. Reverse MR analysis suggested that genetic predisposition to ovarian cancer was associated with lower odds of coronary atherosclerosis(OR = 0.97, 95%CI = 0.94-0.99 ), though the effect size was modest. INTERPRETATION: This comprehensive large-scale MR study provides hypothesis-generating evidence for a bidirectional genetic interplay between cardiovascular and oncological diseases. These findings point to a complex interplay between these conditions, paving the way for future investigations into shared mechanisms and integrated therapeutic strategies. However, all associations should be interpreted as suggestive rather than definitive causal evidence, and validation in independent cohorts is warranted.