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Background: Increased cancer risk has been reported in patients with acute coronary syndrome (ACS)., Objectives: To investigate geographic differences in risk malignancy long after ACS., Methods: We enrolled 586 ACS patients admitted to hospitals in three provinces in the Veneto region of Italy in this prospective study. Patient's residency was classified into three urban and three nearby rural areas., Results: All (except for 3) patients completed the follow-up (22 years or death) and 54 % were living in rural areas. Sixteen patients had pre-existing malignancy, and 106 developed the disease during follow-up. Cancer prevalence was 17 % and 24 % (p = 0.05) and incidence of malignancy was 16 and 21/1000 person-years for urban and rural areas, respectively. In unadjusted logistic regression analysis, cancer risk increased from urban to rural areas (odds ratio [OR] 3.4;95 % confidence interval [CI] 1.7-7.1; p = 0.001), with little change from north to south provinces (OR 1.5;95 % CI 1.0-2.2; p = 0.06). Yet, we found a strong positive interaction between urban-rural areas and provinces (OR 2.1;95 % CI 1.2-3.5; p = 0.003). These results kept true in the fully adjusted model. Unadjusted Cox regression analysis revealed increasing hazards ratios (HRs) for malignancy onset from urban to rural areas (HR 3.0;95 % CI 1.5-6.2; p = 0.02), but not among provinces (HR 1.3;95 % CI 1.0-2.0; p = 0.14). Also, we found a strong positive interaction between geographic areas (HR 2.1;95 % CI 1.3-3.5; p = 0.002), even with a fully adjusted model., Conclusions: The results in unselected real-world patients demonstrate a significant geographic difference in malignancy risk in ACS patients, with the highest risk in the north-rural area.